Polycyclic-carbamoylpyridone compounds and their pharmaceutical use

ABSTRACT

including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, X, Y1, Y2, or L are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

This application claims the benefit of U.S. Provisional Application No.61/845,806 filed Jul. 12, 2013, the disclosure of which is herebyincorporated by reference herein in its entirety.

BACKGROUND Field

Compounds, compositions, and methods for the treatment of humanimmunodeficiency virus (HIV) infection are disclosed. In particular,novel polycyclic carbamoylpyridone compounds and methods for theirpreparation and use as therapeutic or prophylactic agents are disclosed.

Description of the Related Art

Human immunodeficiency virus infection and related diseases are a majorpublic health problem worldwide. Human immunodeficiency virus type 1(HIV-1) encodes three enzymes which are required for viral replication:reverse transcriptase, protease, and integrase. Although drugs targetingreverse transcriptase and protease are in wide use and have showneffectiveness, particularly when employed in combination, toxicity anddevelopment of resistant strains have limited their usefulness (Palella,et al. N. Engl. J Med. (1998) 338:853-860; Richman, D. D. Nature (2001)410:995-1001).

A goal of antiretroviral therapy is to achieve viral suppression in theHIV infected patient. Current treatment guidelines published by theUnited States Department of Health and Human Services provide thatachievement of viral suppression requires the use of combinationtherapies, i.e., several drugs from at least two or more drug classes.(Panel on Antiretroviral Guidelines for Adults and Adolescents.Guidelines for the use of antiretroviral agents in HIV-1-infected adultsand adolescents. Department of Health and Human Services. Available athttp://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf Sectionaccessed Mar. 14, 2013.) In addition, decisions regarding the treatmentof HIV infected patients are complicated when the patient requirestreatment for other medical conditions (Id. at E-12). Because thestandard of care requires the use of multiple different drugs tosuppress HIV, as well as to treat other conditions the patient may beexperiencing, the potential for drug interaction is a criterion forselection of a drug regimen. As such, there is a need for antiretroviraltherapies having a decreased potential for drug interactions.

Accordingly, there is a need for new agents that inhibit the replicationof HIV and that minimize the potential for drug-drug interactions whenco-administered with other drugs.

BRIEF SUMMARY

The present invention is directed to novel polycyclic carbamoylpyridonecompounds, having antiviral activity, including stereoisomers andpharmaceutically acceptable salts thereof, and the use of such compoundsin the treatment of HIV infections. The compounds of the invention maybe used to inhibit the activity of HIV integrase and may be used toreduce HIV replication.

In one embodiment of the present invention, compounds having thefollowing Formula (I) are provided:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

-   -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogens;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl;    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and    -   wherein two R^(a) groups on adjacent carbon atoms, together with        the carbon atoms to which they are attached, form a carbocyclic        ring having the following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In another embodiment of the present invention, compounds havingantiviral activity are provided, the compounds having the followingFormula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

-   -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl, or Y¹ and Y², together with the carbon atom to        which they are attached, form a carbocyclic ring having from 3        to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring        atoms, wherein the carbocyclic or heterocyclic ring is        optionally substituted with one or more R;    -   each R^(c) is, independently, hydrogen, halo, hydroxyl or        C₁₋₄alkyl, or wherein two R^(c) groups, together with the carbon        atom to which they are attached, form C═O;    -   R¹ is optionally substituted aryl or optionally substituted        heteroaryl;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl;    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and    -   wherein two R^(a) groups on adjacent carbon atoms, together with        the carbon atoms to which they are attached, form a carbocyclic        ring having the following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In one embodiment of the present invention, compounds having thefollowing Formula (Ia) are provided:

-   -   or a stereoisomer or pharmaceutically acceptable salt thereof,    -   wherein:    -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogen atoms;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl; and    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and    -   wherein two R^(a) groups on adjacent carbon atoms, together with        the carbon atoms to which they are attached, form a carbocyclic        ring having the following structure:

-   -   wherein each R^(b) is, independently, hydrogen or halo.

In one embodiment of the present invention, compounds having thefollowing Formula (Ib) are provided:

-   -   or a stereoisomer or pharmaceutically acceptable salt thereof,    -   wherein:    -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogen atoms;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl; and    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and

wherein two R^(a) groups on adjacent carbon atoms, together with thecarbon atoms to which they are attached, form a carbocyclic ring havingthe following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In one embodiment of the present invention, compounds having thefollowing Formula (Ic) are provided:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

-   -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogen atoms;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl; and    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and

wherein two R^(a) groups on adjacent carbon atoms, together with thecarbon atoms to which they are attached, form a carbocyclic ring havingthe following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In one embodiment of the present invention, compounds having thefollowing Formula (Id) are provided:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

-   -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogen atoms;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl; and    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and

wherein two R^(a) groups on adjacent carbon atoms, together with thecarbon atoms to which they are attached, form a carbocyclic ring havingthe following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In one embodiment of the present invention, compounds having thefollowing Formula (Ie) are provided:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

-   -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogen atoms;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl; and    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and

wherein two R^(a) groups on adjacent carbon atoms, together with thecarbon atoms to which they are attached, form a carbocyclic ring havingthe following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In another embodiment, a pharmaceutical composition is providedcomprising a compound having Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),or a stereoisomer or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, diluent or excipient.

The invention also provides the use of a pharmaceutical composition asdescribed hereinabove for the treatment of an HIV infection in a humanbeing having or at risk of having the infection.

In yet another embodiment compounds are provided having the followingstructures:

In another embodiment, a method of using a compound having Formula (I),(Ia), (Ib), (Ic), (Id), or (Ie) in therapy is provided. In particular, amethod of treating the proliferation of the HIV virus, treating AIDS, ordelaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human)is provided, comprising administering to the mammal a compound havingFormula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a stereoisomer orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent or excipient.

In another embodiment, use of a compound of Formula (I), (Ia), (Ib),(Ic), (Id), or (Ie) as described herein, or a pharmaceuticallyacceptable salt thereof, for the treatment of an HIV infection in ahuman being having or at risk of having the infection is disclosed.

In another embodiment, the use of a compound of Formula (I), (Ia), (Ib),(Ic), (Id), or (Ie) as described herein, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for thetreatment of an HIV infection in a human being having or at risk ofhaving the infection is disclosed.

In another embodiment, an article of manufacture comprising acomposition effective to treat an HIV infection; and packaging materialcomprising a label which indicates that the composition can be used totreat infection by HIV is disclosed. Exemplary compositions comprise acompound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) according tothis invention or a pharmaceutically acceptable salt thereof.

In still another embodiment, a method of inhibiting the replication ofHIV is disclosed. The method comprises exposing the virus to aneffective amount of the compound of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), or a salt thereof, under conditions where replication of HIV isinhibited.

In another embodiment, the use of a compound of Formula (I), (Ia), (Ib),(Ic), (Id), or (Ie) to inhibit the activity of the HIV integrase enzymeis disclosed.

In another embodiment, the use of a compound of Formula (I), (Ia), (Ib),(Ic), (Id), (Ie), or a salt thereof, to inhibit the replication of HIVis disclosed.

Other embodiments, objects, features and advantages will be set forth inthe detailed description of the embodiments that follows, and in partwill be apparent from the description, or may be learned by practice, ofthe claimed invention. These objects and advantages will be realized andattained by the processes and compositions particularly pointed out inthe written description and claims hereof. The foregoing Summary hasbeen made with the understanding that it is to be considered as a briefand general synopsis of some of the embodiments disclosed herein, isprovided solely for the benefit and convenience of the reader, and isnot intended to limit in any manner the scope, or range of equivalents,to which the appended claims are lawfully entitled.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details. The description belowof several embodiments is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience only and are not to be construedto limit the claims in any way. Embodiments illustrated under anyheading may be combined with embodiments illustrated under any otherheading.

Definitions

Unless the context requires otherwise, throughout the presentspecification and claims, the word “comprise” and variations thereof,such as, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is as “including, but not limited to”.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds),having from one to twelve carbon atoms (C₁-C₁₂ alkyl), preferably one toeight carbon atoms (C₁-C₈ alkyl) or one to six carbon atoms (C₁-C₆alkyl), and which is attached to the rest of the molecule by a singlebond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl,penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. In certain embodiments, “Alkyl” refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, which is saturated, having from one to twelve carbon atoms(C₁-C₁₂ alkyl), or from one to eight carbon atoms (C₁-C₈ alkyl), or fromone to six carbon atoms (C₁-C₆ alkyl), or from one to four carbon atoms(C₁-C₄ alkyl), and which is attached to the rest of the molecule by asingle bond Unless stated otherwise specifically in the specification,an alkyl group may be optionally substituted.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds), andhaving from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, ethenylene, propenylene, n-butenylene,propynylene, n-butynylene, and the like. The alkylene chain is attachedto the rest of the molecule through a single or double bond and to theradical group through a single or double bond. The points of attachmentof the alkylene chain to the rest of the molecule and to the radicalgroup can be through one carbon or any two carbons within the chain.Unless stated otherwise specifically in the specification, an alkylenechain may be optionally substituted.

“Alkoxy” refers to a radical of the formula —OR_(A) where R_(A) is analkyl radical as defined above containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, an alkoxygroup may be optionally substituted.

“Alkylamino” refers to a radical of the formula —NHR_(A) or —NR_(A)R_(A)where each R_(A) is, independently, an alkyl radical as defined abovecontaining one to twelve carbon atoms. Unless stated otherwisespecifically in the specification, an alkylamino group may be optionallysubstituted.

“Thioalkyl” refers to a radical of the formula —SR_(A) where R_(A) is analkyl radical as defined above containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, a thioalkylgroup may be optionally substituted.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems. In a preferred embodiment, the aryl radical is amonocyclic ring system. Aryl radicals include, but are not limited to,aryl radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene,fluorene, as-indacene, s-indacene, indane, indene, naphthalene,phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unlessstated otherwise specifically in the specification, the term “aryl” orthe prefix “ar-” (such as in “aralkyl”) is meant to include arylradicals that are optionally substituted.

“Aralkyl” refers to a radical of the formula —R_(B)—R_(C) where R_(B) isan alkylene chain as defined above and R_(C) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. Unless stated otherwise specifically in the specification, anaralkyl group may be optionally substituted.

“Cycloalkyl” or “carbocyclic ring” refers to a stable non-aromaticmonocyclic or polycyclic hydrocarbon radical consisting solely of carbonand hydrogen atoms, which may include fused or bridged ring systems,having from three to fifteen carbon atoms, preferably having from threeto ten carbon atoms, and which is saturated or unsaturated and attachedto the rest of the molecule by a single bond. In certain preferredembodiments, “Cycloalkyl” or “carbocyclic ring” refers to a stablenon-aromatic monocyclic hydrocarbon radical consisting solely of carbonand hydrogen atoms, having from three to fifteen carbon atoms, or havingfrom three to ten carbon atoms, or having from three to eight carbonatoms and which is saturated or unsaturated and attached to the rest ofthe molecule by a single bond. Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.Unless otherwise stated specifically in the specification, a cycloalkylgroup may be optionally substituted.

“Cycloalkylalkyl” refers to a radical of the formula —R_(B)R_(D) whereR_(B) is an alkylene chain as defined above and R_(D) is a cycloalkylradical as defined above. Unless stated otherwise specifically in thespecification, a cycloalkylalkyl group may be optionally substituted.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. Unless stated otherwise specifically in the specification, ahaloalkyl group may be optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a stable 3- to18-membered non-aromatic ring radical which consists of two to twelvecarbon atoms and from one to six heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur. Unless stated otherwisespecifically in the specification, the heterocyclyl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems; and the nitrogen, carbon orsulfur atoms in the heterocyclyl radical may be optionally oxidized; thenitrogen atom may be optionally quaternized; and the heterocyclylradical may be partially or fully saturated. Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, a heterocyclyl group may be optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. Unless stated otherwisespecifically in the specification, an N-heterocyclyl group may beoptionally substituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(B)R_(E) whereR_(B) is an alkylene chain as defined above and R_(E) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. Unless stated otherwisespecifically in the specification, a heterocyclylalkyl group may beoptionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; the nitrogen, carbon or sulfur atoms in the heteroaryl radicalmay be optionally oxidized; and the nitrogen atom may be optionallyquaternized. In certain preferred embodiments, the heteroaryl radicalmay be a monocyclic ring system; the nitrogen, carbon or sulfur atoms inthe heteroaryl radical may be optionally oxidized; and the nitrogen atommay be optionally quaternized. Examples include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl,benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group may be optionallysubstituted.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. Unless stated otherwise specifically inthe specification, an N-heteroaryl group may be optionally substituted.

“Heteroarylalkyl” refers to a radical of the formula —R_(B)R_(F) whereR_(B) is an alkylene chain as defined above and R_(F) is a heteroarylradical as defined above. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group may be optionally substituted.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl)wherein at least one hydrogen atom is replaced by a bond to anon-hydrogen atoms such as, but not limited to: a halogen atom such asF, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups,alkoxy groups, and ester groups; a sulfur atom in groups such as thiolgroups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxidegroups; a nitrogen atom in groups such as amines, amides, alkylamines,dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides,imides, and enamines; a silicon atom in groups such as trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced by a higher-order bond (e.g., a double- ortriple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl,and ester groups; and nitrogen in groups such as imines, oximes,hydrazones, and nitriles. For example, “substituted” includes any of theabove groups in which one or more hydrogen atoms are replaced with—NR_(G)R_(H), —NR_(G)C(═O)R_(H), —NR_(G)C(═O)NR_(G)R_(H),—NR_(G)C(═O)OR_(H), —NR_(G)C(═NR_(g))NR_(G)R_(H), —NR_(G) SO₂R_(H),—OC(═O)NR_(G)R_(H), —OR_(G), —SR_(G), —SOR_(G), —SO₂R_(G), —OSO₂R_(G),—SO₂OR_(G), ═NSO₂R_(G), and —SO₂NR_(G)R_(H). “Substituted also means anyof the above groups in which one or more hydrogen atoms are replacedwith —C(═O)R_(G), —C(═O)OR_(G), —C(═O)NR_(G)R_(H), —CH₂SO₂R_(G),—CH₂SO₂NR_(G)R_(H). In the foregoing, R_(G) and R_(H) are the same ordifferent and independently hydrogen, alkyl, alkoxy, alkylamino,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl. “Substituted” further means any ofthe above groups in which one or more hydrogen atoms are replaced by abond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo,alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkylgroup. In addition, each of the foregoing substituents may also beoptionally substituted with one or more of the above substituents.

The term “protecting group,” as used herein, refers to a labile chemicalmoiety which is known in the art to protect reactive groups includingwithout limitation, hydroxyl and amino groups, against undesiredreactions during synthetic procedures. Hydroxyl and amino groupsprotected with a protecting group are referred to herein as “protectedhydroxyl groups” and “protected amino groups”, respectively. Protectinggroups are typically used selectively and/or orthogonally to protectsites during reactions at other reactive sites and can then be removedto leave the unprotected group as is or available for further reactions.Protecting groups as known in the art are described generally in Greeneand Wuts, Protective Groups in Organic Synthesis, 3rd edition, JohnWiley & Sons, New York (1999). Generally, groups are protected orpresent as a precursor that will be inert to reactions that modify otherareas of the parent molecule for conversion into their final groups atan appropriate time. Further representative protecting or precursorgroups are discussed in Agrawal, et al., Protocols for OligonucleotideConjugates, Eds, Humana Press; New Jersey, 1994; Vol. 26 pp. 1-72.Examples of “hydroxyl protecting groups” include, but are not limitedto, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl,p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl,diphenyl-methyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl,triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl (TBDPS),triphenylsilyl, benzoylformate, acetate, chloroacetate,trichloroacetate, trifluoroacetate, pivaloate, benzoate,p-phenylbenzoate, 9-fluorenylmethyl carbonate, mesylate and tosylate.Examples of “amino protecting groups” include, but are not limited to,carbamate-protecting groups, such as 2-trimethylsilylethoxycarbonyl(Teoc), 1-methyl-1-(4-biphenylyl)ethoxycarbonyl (Bpoc), t-butoxycarbonyl(BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc),and benzyloxycarbonyl (Cbz); amide protecting groups, such as formyl,acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl;sulfonamide-protecting groups, such as 2-nitrobenzenesulfonyl; and imineand cyclic imide protecting groups, such as phthalimido anddithiasuccinoyl.

The invention disclosed herein is also meant to encompass allpharmaceutically acceptable compounds of Formulas (I), (Ia), (Ib), (Ic),(Id), and (Ie), being isotopically-labeled by having one or more atomsreplaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. These radiolabeled compounds could be useful to helpdetermine or measure the effectiveness of the compounds, bycharacterizing, for example, the site or mode of action, or bindingaffinity to pharmacologically important site of action. Certainisotopically-labeled compounds of Formulas (I), (Ia), (Ib), (Ic), (Id),and (Ie), for example, those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability. For example, in vivo half-life may increase or dosagerequirements may be reduced. Thus, heavier isotopes may be preferred insome circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof Formulas (I), (Ia), (Ib), (Ic), (Id), and (Ie), can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the Examples as set outbelow using an appropriate isotopically-labeled reagent in place of thenon-labeled reagent previously employed.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising administering a compound of thisinvention to a mammal for a period of time sufficient to yield ametabolic product thereof. Such products are typically identified byadministering a radiolabeled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

Examples of “pharmaceutically acceptable salts” of the compoundsdisclosed herein include salts derived from an appropriate base, such asan alkali metal (for example, sodium), an alkaline earth metal (forexample, magnesium), ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl).Pharmaceutically acceptable salts of a nitrogen atom or an amino groupinclude for example salts of organic carboxylic acids such as acetic,benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic,lactobionic and succinic acids; organic sulfonic acids, such asmethanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonicacids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric,phosphoric and sulfamic acids. Pharmaceutically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NX₄ ⁺ (wherein X isindependently selected from H or a C₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compoundsdisclosed herein will typically be pharmaceutically acceptable, i.e.they will be salts derived from a physiologically acceptable acid orbase. However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),or another compound of the invention. All salts, whether or not derivedfrom a physiologically acceptable acid or base, are within the scope ofthe present invention.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines. Finally, it is to beunderstood that the compositions herein comprise compounds disclosedherein in their un-ionized, as well as zwitterionic form, andcombinations with stoichiometric amounts of water as in hydrates.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Effective amount” or “therapeutically effective amount” refers to anamount of a compound according to the invention, which when administeredto a patient in need thereof, is sufficient to effect treatment fordisease-states, conditions, or disorders for which the compounds haveutility. Such an amount would be sufficient to elicit the biological ormedical response of a tissue system, or patient that is sought by aresearcher or clinician. The amount of a compound according to theinvention which constitutes a therapeutically effective amount will varydepending on such factors as the compound and its biological activity,the composition used for administration, the time of administration, theroute of administration, the rate of excretion of the compound, theduration of the treatment, the type of disease-state or disorder beingtreated and its severity, drugs used in combination with orcoincidentally with the compounds of the invention, and the age, bodyweight, general health, sex and diet of the patient. Such atherapeutically effective amount can be determined routinely by one ofordinary skill in the art having regard to their own knowledge, thestate of the art, and this disclosure.

The term “treatment” as used herein is intended to mean theadministration of a compound or composition according to the presentinvention to alleviate or eliminate symptoms of HIV infection and/or toreduce viral load in a patient. The term “treatment” also encompassesthe administration of a compound or composition according to the presentinvention post-exposure of the individual to the virus but before theappearance of symptoms of the disease, and/or prior to the detection ofthe virus in the blood, to prevent the appearance of symptoms of thedisease and/or to prevent the virus from reaching detectible levels inthe blood, and the administration of a compound or composition accordingto the present invention to prevent perinatal transmission of HIV frommother to baby, by administration to the mother before giving birth andto the child within the first days of life.

The term “antiviral agent” as used herein is intended to mean an agent(compound or biological) that is effective to inhibit the formationand/or replication of a virus in a human being, including but notlimited to agents that interfere with either host or viral mechanismsnecessary for the formation and/or replication of a virus in a humanbeing.

The term “inhibitor of HIV replication” as used herein is intended tomean an agent capable of reducing or eliminating the ability of HIV toreplicate in a host cell, whether in vitro, ex vivo or in vivo.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

Compounds

As noted above, in one embodiment of the present invention, compoundshaving antiviral activity are provided, the compounds having thefollowing Formula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

-   -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogens;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl;    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and

wherein two R^(a) groups on adjacent carbon atoms, together with thecarbon atoms to which they are attached, form a carbocyclic ring havingthe following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In one embodiment of the present invention, compounds having thefollowing Formula (Ia) are provided:

-   -   or a stereoisomer or pharmaceutically acceptable salt thereof,    -   wherein:    -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogen atoms;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl; and    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and    -   wherein two R^(a) groups on adjacent carbon atoms, together with        the carbon atoms to which they are attached, form a carbocyclic        ring having the following structure:

-   -   wherein each R^(b) is, independently, hydrogen or halo.

In one embodiment of the present invention, compounds having thefollowing Formula (Ib) are provided:

-   -   or a stereoisomer or pharmaceutically acceptable salt thereof,    -   wherein:    -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogen atoms;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl; and    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and

wherein two R^(a) groups on adjacent carbon atoms, together with thecarbon atoms to which they are attached, form a carbocyclic ring havingthe following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In one embodiment of the present invention, compounds having thefollowing Formula (Ic) are provided:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

-   -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogen atoms;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl; and    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and

wherein two R^(a) groups on adjacent carbon atoms, together with thecarbon atoms to which they are attached, form a carbocyclic ring havingthe following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In one embodiment of the present invention, compounds having thefollowing Formula (Id) are provided:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

-   -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogen atoms;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl; and    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and

wherein two R^(a) groups on adjacent carbon atoms, together with thecarbon atoms to which they are attached, form a carbocyclic ring havingthe following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In one embodiment of the present invention, compounds having thefollowing Formula (Ie) are provided:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

-   -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl;    -   R¹ is phenyl substituted with one to three halogen atoms;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl; and    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and

wherein two R^(a) groups on adjacent carbon atoms, together with thecarbon atoms to which they are attached, form a carbocyclic ring havingthe following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In another embodiment, X is —O—. In another embodiment, X is —NH—. Inanother embodiment, X is —CH₂—. In another embodiment, X is a bond.

In another embodiment, Y¹ is C₁₋₄alkyl and Y² is hydrogen. In anotherembodiment, Y¹ is methyl and Y² is hydrogen. In another embodiment, Y¹is C₁₋₄haloalkyl and Y² is hydrogen. In another embodiment, Y¹ is CF₃and Y² is hydrogen. In another embodiment, Y¹ is hydrogen, methyl or CF₃and Y² is hydrogen. In another embodiment, Y¹ and Y² are both hydrogen.

In another embodiment, R¹ is substituted with one halogen. In a furtherembodiment, R¹ is 4-fluorophenyl or 2-fluorophenyl.

In another embodiment, R¹ is substituted with two halogens. In a furtherembodiment, R¹ is 2,4-difluorophenyl, 2,3-difluorophenyl,2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl,2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. In still a furtherembodiment, R¹ is 2,4-difluorophenyl.

In another embodiment, R¹ is substituted with three halogens. In afurther embodiment, R¹ is 2,4,6-trifluorophenyl or2,3,4-trifluorophenyl. In still a further embodiment, R¹ is2,4,6-trifluorophenyl.

In another embodiment, each R^(b) is independently hydrogen. In anotherembodiment, each R^(b) is independently halogen. In a furtherembodiment, each R^(b) is fluoro.

In one embodiment, a pharmaceutical composition is provided comprising acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or a stereoisomeror pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent or excipient.

Another embodiment is provided comprising a method of treating orpreventing an HIV infection in a human having or at risk of having theinfection by administering to the human a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or apharmaceutical composition thereof.

In another embodiment, the use of a compound of Formula (I), (Ia), (Ib),(Ic), (Id), (Ie), or a pharmaceutical composition thereof for thetreatment or prevention of an HIV infection in a human having or at riskof having the infection.

As further noted above, in another embodiment of the present invention,compounds having antiviral activity are provided, the compounds havingthe following Formula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

-   -   Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or        C₁₋₃haloalkyl, or Y¹ and Y², together with the carbon atom to        which they are attached, form a carbocyclic ring having from 3        to 6 ring atoms or a heterocyclic ring having from 3 to 6 ring        atoms, wherein the carbocyclic or heterocyclic ring is        optionally substituted with one or more R^(c);    -   each R^(c) is, independently, hydrogen, halo, hydroxyl or        C₁₋₄alkyl, or wherein two R^(C) groups, together with the carbon        atom to which they are attached, form C═O;    -   R¹ is optionally substituted aryl or optionally substituted        heteroaryl;    -   X is —O—, —NR²—, —CHR³— or a bond;    -   R² and R³ are each, independently, hydrogen or C₁₋₃alkyl;    -   L is —C(R^(a))₂C(R^(a))₂—; and    -   each R^(a) is, independently, hydrogen, halo, hydroxyl, or        C₁₋₄alkyl, and    -   wherein two R^(a) groups on adjacent carbon atoms, together with        the carbon atoms to which they are attached, form a carbocyclic        ring having the following structure:

wherein each R^(b) is, independently, hydrogen or halo.

In another embodiment, compounds are provided having one of thefollowing Formulas (II-A), (II-B), (II-C) or (II-D):

In another embodiment, compounds are provided having one of thefollowing Formulas (II-E), (II-F), (II-G), or (II-H):

In another embodiment, X is —O—. In another embodiment, X is —NH—. Inanother embodiment, X is —CH₂—. In another embodiment, X is a bond.

In another embodiment, R¹ is phenyl. In another embodiment, R¹ ispyridinyl.

In another embodiment, R¹ is substituted with at least one halogen.

In another embodiment, R¹ is substituted with one halogen. In a furtherembodiment, R¹ is 4-fluorophenyl or 2-fluorophenyl.

In another embodiment, R¹ is substituted with two halogens. In a furtherembodiment, R¹ is 2,4-difluorophenyl, 2,3-difluorophenyl,2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl,2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. In still a furtherembodiment, R¹ is 2,4-difluorophenyl.

In another embodiment, R¹ is substituted with three halogens. In afurther embodiment, R¹ is 2,4,6-trifluorophenyl or2,3,4-trifluorophenyl. In still a further embodiment, R¹ is2,4,6-trifluorophenyl.

In another embodiment, each R^(b) is independently hydrogen. In anotherembodiment, each R^(b) is independently halogen. In a furtherembodiment, each R^(b) is fluoro.

In one embodiment, a pharmaceutical composition is provided comprising acompound of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie),(II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), and (II-H), or astereoisomer or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, diluent or excipient.

Another embodiment is provided comprising a method of treating orpreventing an HIV infection in a human having or at risk of having theinfection by administering to the human a therapeutically effectiveamount of a compound of any one of Formulas (I), (Ia), (Ib), (Ic), (Id),(Ie), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), and(II-H), or a pharmaceutical composition thereof.

In another embodiment, the use of a compound of Formula any one ofFormulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II-A), (II-B), (II-C),(II-D), (II-E), (II-F), (II-G), and (II-H), or a pharmaceuticalcomposition thereof for the treatment or prevention of an HIV infectionin a human having or at risk of having the infection.

It is understood that any embodiment of the compounds of any one ofFormulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II-A), (II-B), (II-C),(II-D), (II-E), (II-F), (II-G), and (II-H), as set forth above, and anyspecific substituent set forth herein for a R¹, R², R³, R^(a), R^(b),R^(c), X, Y¹, Y², or L group in the compounds of Formulas (I), (Ia),(Ib), (Ic), (Id), or (Ie), as set forth above, may be independentlycombined with other embodiments and/or substituents of compounds of anyone of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II-A), (II-B),(II-C), (II-D), (II-E), (II-F), (II-G), and (II-H), to form embodimentsof the inventions not specifically set forth above. In addition, in theevent that a list of substitutents is listed for any particular R¹, R²,R³, R^(a), R^(b), R^(c), X, Y¹, Y², or L in a particular embodimentand/or claim, it is understood that each individual substituent may bedeleted from the particular embodiment and/or claim and that theremaining list of substituents will be considered to be within the scopeof the invention.

Pharmaceutical Compositions

For the purposes of administration, in certain embodiments, thecompounds described herein are administered as a raw chemical or areformulated as pharmaceutical compositions. Pharmaceutical compositionsof the present invention comprise a compound of Formulas (I), (Ia),(Ib), (Ic), (Id), (Ie), and a pharmaceutically acceptable carrier,diluent or excipient. The compound of Formulas (I), (Ia), (Ib), (Ic),(Id), (Ie), is present in the composition in an amount which iseffective to treat a particular disease or condition of interest. Theactivity of compounds of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), canbe determined by one skilled in the art, for example, as described inthe Examples below. Appropriate concentrations and dosages can bereadily determined by one skilled in the art.

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. Pharmaceutical compositions of the invention are formulatedso as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

The pharmaceutical compositions of the invention may be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy.

Combination Therapy

In one embodiment, a method for treating or preventing an HIV infectionin a human having or at risk of having the infection is provided,comprising administering to the human a therapeutically effective amountof a compound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with a therapeutically effective amount of oneor more (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents. In one embodiment, a method for treating an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, one or two, or one tothree) additional therapeutic agents.

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more (e.g., one, two, three, one or two, or oneto three) additional therapeutic agents, and a pharmaceuticallyacceptable carrier, diluent or excipient are provided.

In one embodiment, combination pharmaceutical agents comprising acompound disclosed herein, or a pharmaceutically acceptable saltthereof, in combination with one or more (e.g., one, two, three, one ortwo, or one to three) additional therapeutic agents are provided.

In the above embodiments, the additional therapeutic agent may be ananti-HIV agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting of HIV proteaseinhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside or nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, HIV non-catalytic site (or allosteric) integraseinhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors(i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors,compounds that target the HIV capsid (“capsid inhibitors”; e.g., capsidpolymerization inhibitors or capsid disrupting compounds such as thosedisclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489(University of Pennsylvania), and WO 2013/006792 (Pharma Resources),pharmacokinetic enhancers, and other drugs for treating HIV, andcombinations thereof. In further embodiments, the additional therapeuticagent is selected from one or more of:

(1) HIV protease inhibitors selected from the group consisting ofamprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir,nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;

(2) HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase selected from the group consisting of capravirine,emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A,etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120,rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK-453061), RDEA806,KM023 and MK-1439;

(3) HIV nucleoside or nucleotide inhibitors of reverse transcriptaseselected from the group consisting of zidovudine, emtricitabine,didanosine, stavudine, zalcitabine, lamivudine, abacavir, abavavirsulfate, amdoxovir, elvucitabine, alovudine, MIV-210, ±-FTC, D-d4FC,emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754),KP-1461, GS-9131 (Gilead Sciences) and fosalvudine tidoxil (formerly HDP99.0003), tenofovir, tenofovir disoproxil fumarate, tenofoviralafenamide (Gilead Sciences), tenofovir alafenamide hemifumarate(Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovirdipivoxil, CMX-001 (Chimerix) or CMX-157 (Chimerix);

(4) HIV integrase inhibitors selected from the group consisting ofcurcumin, derivatives of curcumin, chicoric acid, derivatives ofchicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, andL-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA011, elvitegravir, dolutegravir and GSK-744;

(5) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI)including, but not limited to, BI-224436, CX0516, CX05045, CX14442,compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO2012/003498 (Gilead Sciences) each of which is incorporated byreferences in its entirety herein;

(6) gp41 inhibitors selected from the group consisting of enfuvirtide,sifuvirtide, albuvirtide, FB006M, and TRI-1144;

(7) the CXCR4 inhibitor AMD-070;

(8) the entry inhibitor SP01A;

(9) the gp120 inhibitor BMS-488043;

(10) the G6PD and NADH-oxidase inhibitor immunitin;

(11) CCR5 inhibitors selected from the group consisting of aplaviroc,vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798(Pfizer), and CCR5mAb004;

(12) CD4 attachment inhibitors selected from the group consisting ofibalizumab (TMB-355) and BMS-068 (BMS-663068);

(13) pharmacokinetic enhancers selected from the group consisting ofcobicistat and SPI-452; and

(14) other drugs for treating HIV selected from the group consisting ofBAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1,PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221HIV, DEBIO-025, BAY 50-4798, MDXO10 (ipilimumab), PBS 119, ALG 889, andPA-1050040 (PA-040), and combinations thereof.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The two, three, fouror more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, or they canbe selected from different classes of therapeutic agents. In a specificembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase and an HIV non-nucleosideinhibitor of reverse transcriptase. In another specific embodiment, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with an HIV nucleoside or nucleotide inhibitor ofreverse transcriptase, and an HIV protease inhibiting compound. In afurther embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, an HIV non-nucleosideinhibitor of reverse transcriptase, and an HIV protease inhibitingcompound. In an additional embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase, an HIVnon-nucleoside inhibitor of reverse transcriptase, and a pharmacokineticenhancer. In another embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with two HIVnucleoside or nucleotide inhibitor of reverse transcriptase.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, tenofovir, tenofovir disoproxil fumarate, tenofoviralafenamide, or tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofoviralafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofoviralafenamide, and tenofovir alafenamide hemifumarate and a secondadditional therapeutic agent selected from the group consisting ofemtricitibine and lamivudine.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, andtenofovir alafenamide hemifumarate and a second additional therapeuticagent, wherein the second additional therapeutic agent is emtricitibine.

In certain embodiments, when a compound disclosed herein is combinedwith one or more additional therapeutic agents as described above, thecomponents of the composition are administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations.

In certain embodiments, a compound disclosed herein is combined with oneor more additional therapeutic agents in a unitary dosage form forsimultaneous administration to a patient, for example as a solid dosageform for oral administration.

In certain embodiments, a compound disclosed herein is administered withone or more additional therapeutic agents. Co-administration of acompound disclosed herein with one or more additional therapeutic agentsgenerally refers to simultaneous or sequential administration of acompound disclosed herein and one or more additional therapeutic agents,such that therapeutically effective amounts of the compound disclosedherein and one or more additional therapeutic agents are both present inthe body of the patient.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents, for example,administration of the compound disclosed herein within seconds, minutes,or hours of the administration of one or more additional therapeuticagents. For example, in some embodiments, a unit dose of a compounddisclosed herein is administered first, followed within seconds orminutes by administration of a unit dose of one or more additionaltherapeutic agents. Alternatively, in other embodiments, a unit dose ofone or more additional therapeutic agents is administered first,followed by administration of a unit dose of a compound disclosed hereinwithin seconds or minutes. In some embodiments, a unit dose of acompound disclosed herein is administered first, followed, after aperiod of hours (e.g., 1-12 hours), by administration of a unit dose ofone or more additional therapeutic agents. In other embodiments, a unitdose of one or more additional therapeutic agents is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound disclosed herein.

The following Examples illustrate various methods of making compounds ofthis invention, i.e., compound of Formula (I):

wherein R¹, X, W, Y¹, Y², or L are as defined above. It is understoodthat one skilled in the art may be able to make these compounds bysimilar methods or by combining other methods known to one skilled inthe art. It is also understood that one skilled in the art would be ableto make, in a similar manner as described below, other compounds ofFormulas (I), (Ia), (Ib), (Ic), (Id), (Ie), not specifically illustratedbelow by using the appropriate starting components and modifying theparameters of the synthesis as needed. In general, starting componentsmay be obtained from sources such as Sigma Aldrich, Lancaster Synthesis,Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,for example, Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5th edition (Wiley, December 2000)) or prepared as describedherein.

The following examples are provided for purposes of illustration, notlimitation.

EXAMPLES Representative Compounds Example 1 Preparation of Compound 1(1aS,2S,3aR,12R,12aR)—N—((S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethyl)-9-hydroxy-8,10-dioxo-1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-methanocyclopropa[e]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-7-carboxamide

Step 1

A 50-mL 1-neck round bottom flask was charged with reactant 1-A (0.11 g,0.22 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treatedwith methanesulfonic acid (0.05 mL), sealed with a yellow cap, andheated to 70° C. After 16 hours, the mixture was cooled to afford acrude solution of intermediate 1-B. LCMS-ESI⁺ (m/z): [M+H]⁺ calculatedfor C₁₈H₁₉F₂N₂O₇: 481; found: 481.

Step 2

The crude mixture from the previous step contains reactant 1-B inacetonitrile (1.5 mL) and acetic acid (0.2 mL). 1-C (WO2013090929A1,0.032 g, 0.22 mmol) and K₂CO₃ (0.15 g, 1.1 mmol) were added to thereaction mixture. The reaction mixture was sealed and heated to 70° C.After 3 hours, the reaction mixture was diluted with EtOAc (50 mL),washed with saturated NaHCO₃ and dried over Na₂SO₄. After concentration,the crude was purified by column chromatography on silica gel withhexane-EtOAc to obtain 1-D. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated forC₂₁H₂₀F₂N₃O₅: 526; found: 526.

Step 3

A 50-mL 1-neck round bottom flask was charged with reactant 1-D (0.02 g,0.038 mmol) and magnesium bromide (0.02 g, 0.10 mmol) in acetonitrile (2mL). The reaction mixture was heated to 50° C. After 10 minutes, thereaction mixture was cooled to 0° C. and 1 N hydrochloric acid (0.5 mL)was added in. There were some solids formed and stuck on the flask wall.Add more water (˜5 mL). The solid was filtrated and washed with water.Then the solid was transferred to the barcode vial and underlyophilization overnight to afford compound 1. ¹H NMR (400 MHz,Chloroform-d) δ 12.38 (s, 1H), 11.25 (d, J=9.3 Hz, 1H), 8.24 (s, 1H),7.48 (q, J=7.8 Hz, 1H), 7.06-6.69 (m, 2H), 6.30-5.98 (m, 1H), 5.85 (s,1H), 4.18 (s, 1H), 3.93 (d, J=34.6 Hz, 2H), 2.04-1.35 (m, 5H), 0.80 (d,J=7.3 Hz, 1H), 0.63-0.43 (m, 1H). ¹⁹F NMR (377 MHz, Chloroform-d) δ−75.29 (t, J=7.5 Hz, 3 F), −107.18-−109.52 (m, 1F), −113.01 (m, 1F).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₅: 512; found: 512.

Example 2 Preparation of Compound 2(1aR,2R,3aS,12S,12aS)—N—((S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethyl)-9-hydroxy-8,8,10-dioxo-1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-methanocyclopropa[e]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-7-carboxamide

Step 1

A 50-mL 1-neck round bottom flask was charged with reactant 1-A (0.11 g,0.22 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treatedwith methanesulfonic acid (0.05 mL), sealed with a yellow cap, andheated to 70° C. After 16 hours, the mixture was cooled to afford acrude solution of intermediate 1-B. LCMS-ESI (m/z): [M+H]⁺ calculatedfor C₁₈H₁₉F₂N₂O₇: 481; found: 481.

Step 2

The crude mixture from the previous step contains reactant 1-B inacetonitrile (1.5 mL) and acetic acid (0.2 mL). 2-A (0.032 g, 0.22 mmol)and K₂CO₃ (0.15 g, 1.1 mmol) were added to the reaction mixture. Thereaction mixture was sealed and heated to 70° C. After 3 hours, thereaction mixture was diluted with EtOAc (50 mL), washed with saturatedNaHCO₃ and dried over Na₂SO₄. After concentration, the crude waspurified by column chromatography on silica gel with hexane-EtOAc toobtain 2-B. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₅: 526;found: 526.

Step 3

A 50-mL 1-neck round bottom flask was charged with reactant 2-B (0.03 g,0.058 mmol) and magnesium bromide (0.03 g, 0.15 mmol) in acetonitrile (2mL). The reaction mixture was heated to 50° C. After 10 minutes, thereaction mixture was cooled to 0° C. and 1 N hydrochloric acid (0.5 mL)was added in. There were some solid formed and stuck on the flask wall.Add more water (˜5 mL). The solid was filtrated and washed with water.Then the solid was transferred to the barcode vial and underlyophilization overnight to afford compound 2. ¹H NMR (400 MHz,Chloroform-d) δ 12.44 (s, 1H), 11.32 (d, J=9.4 Hz, 1H), 8.29 (s, 1H),7.81-7.39 (m, 1H), 7.19-6.67 (m, 2H), 6.42-6.04 (m, 1H), 5.94 (d, J10=9.3 Hz, 1H), 4.84-4.43 (m, 1H), 4.26 (d, J=12.6 Hz, 1H), 4.02 (t,J=10.5 Hz, 1H), 2.08-1.38 (m, 5H), 0.88 (q, J=7.2 Hz, 1H), 0.60 (dd,J=6.3, 3.3 Hz, 1H). ¹⁹F NMR (377 MHz, Chloroform-d) δ −75.25 (t, J=6.5Hz, 3 F), −106.94-−109.63 (m, 1F), −112.11 (m, 1F). LCMS-ESI⁺ (m/z):[M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₅: 512; found: 512.

Example 3 Preparation of Compound 3(1aS,2S,3aR,12R,12aR)—N—((R)-1-(2,4-difluorophenyl)ethyl)-9-hydroxy-8,10-dioxo-1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-methanocyclopropa[e]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-7-carboxamide

Step 1

A 50-mL 1-neck round bottom flask was charged with reactant 3-A (0.11 g,0.24 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treatedwith methanesulfonic acid (0.05 mL), sealed with a yellow cap, andheated to 70° C. After 16 hours, the mixture was cooled to afford acrude solution of intermediate 3-B. LCMS-ESI⁺ (m/z): [M+H]⁺ calculatedfor C₁₈H₁₉F₂N₂O₇: 427; found: 427.

Step 2

The crude mixture from the previous step contains reactant 3-B inacetonitrile (1.5 mL) and acetic acid (0.2 mL). 1-C (0.036 g, 0.24 mmol)and K₂CO₃ (0.167 g, 1.2 mmol) were added to the reaction mixture. Thereaction mixture was sealed and heated to 70° C. After 3 hours, thereaction mixture was diluted with EtOAc (50 mL), washed with saturatedNaHCO₃ and dried over Na₂SO₄. After concentration, the crude waspurified by column chromatography on silica gel with hexane-EtOAc toobtain 3-C. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₅: 472;found: 472.

Step 3

A 50-mL 1-neck round bottom flask was charged with reactant 3-C (0.03 g,0.058 mmol) and magnesium bromide (0.03 g, 0.15 mmol) in acetonitrile (2mL). The reaction mixture was heated to 50° C. After 10 minutes, thereaction mixture was cooled to 0° C. and 1 N hydrochloric acid (0.5 mL)was added in. There were some solid formed and stuck on the flask wall.Add more water (˜5 mL). The solid was filtrated and washed with water.Then the solid was transferred to the barcode vial and underlyophilization overnight to afford compound 3. ¹H NMR (400 MHz,Chloroform-d) δ 12.35 (s, 1H), 10.57 (s, 1H), 8.26 (s, 1H), 7.61-7.28(m, 1H), 7.00-6.65 (m, 2H), 5.89 (s, 1H), 5.45 (d, J=10.2 Hz, 1H),5.34-5.13 (m, 1H), 4.58 (d, J=2.0 Hz, 1H), 4.20 (s, 1H), 4.02 (d, J=7.2Hz, 2H), 2.12-1.43 (m, 6H), 0.87 (d, J=7.5 Hz, 1H), 0.60 (s, 1H). ¹⁹FNMR (376 MHz, Methanol-d₄) δ −113.03 (m, 1F), −114.92 (m, 1F). LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₅: 458; found: 458.

Example 4 Preparation of Compound 4(1aR,2R,3aS,12S,12aS)—N—((R)-1-(2,4-difluorophenyl)ethyl)-9-hydroxy-8,10-dioxo-1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-methanocyclopropa[e]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-7-carboxamide

Step 1

A 50-mL 1-neck round bottom flask was charged with reactant 3-A (0.11 g,0.24 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treatedwith methanesulfonic acid (0.05 mL), sealed with a yellow cap, andheated to 70° C. After 16 hours, the mixture was cooled to afford acrude solution of intermediate 3-B. LCMS-ESI⁺ (m/z): [M+H]⁺ calculatedfor C₁₈H₁₉F₂N₂O₇: 427; found: 427.

Steps 2

The crude mixture from the previous step contains reactant 3-B inacetonitrile (1.5 mL) and acetic acid (0.2 mL). 2-A (0.036 g, 0.24 mmol)and K₂CO₃ (0.167 g, 1.2 mmol) were added to the reaction mixture. Thereaction mixture was sealed and heated to 70° C. After 3 hours, thereaction mixture was diluted with EtOAc (50 mL), washed with sat NaHCO₃and dried over Na₂SO₄. After concentration, the crude was purified bycolumn chromatography on silica gel with hexane-EtOAc to obtain 4-A.LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₅: 472; found: 472.

Steps 3

A 50-mL 1-neck round bottom flask was charged with reactant 4-A (0.03 g,0.058 mmol) and magnesium bromide (0.03 g, 0.15 mmol) in acetonitrile (2mL). The reaction mixture was heated to 50° C. After 10 minutes, thereaction mixture was cooled to 0° C. and 1 N hydrochloric acid (0.5 mL)was added in. There were some solid formed and stuck on the flask wall.Add more water (˜5 mL). The solid was filtrated and washed with water.Then the solid was transferred to the barcode vial and underlyophilization overnight to afford compound 4. ¹H NMR (400 MHz,Chloroform-d) δ 12.35 (s, 1H), 10.56 (s, 1H), 8.26 (s, 1H), 7.37 (s,1H), 7.00-6.63 (m, 2H), 5.89 (s, 1H), 5.45 (d, J=11.0 Hz, 1H), 5.34-5.00(m, 1H), 4.58 (d, J=2.4 Hz, 1H), 4.21 (s, 1H), 4.03 (s, 2H), 2.10-1.43(m, 6H), 0.87 (d, J=7.5 Hz, 1H), 0.60 (s, 1H). ¹⁹F NMR (376 MHz,Chloroform-d) δ −113.00 (m, 1F), −115.00 (m, 1F). LCMS-ESI⁺ (m/z):[M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₅: 458; found: 458.

Example 5 Preparation of Compound 5(1aR,2R,12S,12aS)—N-(2,4-difluorobenzyl)-1,1-difluoro-9-hydroxy-8,10-dioxo-1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-methanocyclopropa[e]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-7-carboxamide

Step 1

A mixture of compound 5-A (1252 mg, 6.796 mmol), phthalimide (1631 mg,11.09 mmol), and PPh₃ (3939 mg, 15.02 mmol) in THF (75 mL) was stirredat 0° C. bath as DIAD (3.0 mL, 15.24 mmol) was added. After addition,the mixture was stirred at room temperature. After 3 hours, the mixturewas concentrated and the residue was triturated with ethyl ether (˜100mL) at 0° C. bath for 10 minutes before filtration. After the filtratewas concentrated, the residue was dissolved in ethyl ether (˜50 ml)again and the insoluble material was filtered off. The filtrate wasconcentrated, and the residue was purified by CombiFlash usinghexanes-ethyl acetate as eluents to obtain compound 5-B. ¹H NMR (400MHz, CDCl₃) δ 7.91-7.75 (m, 2H), 7.75-7.64 (m, 2H), 6.06 (dt, J=5.8, 2.0Hz, 1H), 5.99 (dt, J=5.7, 1.7 Hz, 1H), 5.64 (ddq, J=7.4, 5.5, 1.6 Hz,1H), 5.25 (tq, J=6.7, 2.1 Hz, 1H), 2.90 (dt, J=13.6, 8.1 Hz, 1H),2.22-2.00 (m, 1H), 1.21 (d, J=1.3 Hz, 9H).

Step 2

A mixture of compound 5-B (750 mg, 2.394 mmol) and NaF (1.0 mg, 0.024mmol) in toluene (1 mL) was stirred at 110° C. as FSO₂CF₂COOTMS (0.95mL, 4.821 mmol) was added using syringe drive over 5 hours. The reactionmixture was treated with NaHCO₃ solution and the organic solublematerial was extracted with CH₂Cl₂ (×2). After the combined extractswere dried (Na₂SO₄) and concentrated, the residue was separated withCombiflash using hexanes-ethyl acetate as eluents to get partially purecompound 5-C and the reactant.

The recovered reactant (577 mg) with NaF (1.0 mg, 0.024 mmol) in toluene(1 mL) was again stirred at 110° C. as FSO₂CF₂COOTMS (3 mL, 15.22 mmol)was added using syringe drive over 15 hours. The reaction mixture wasworked up as described previously and the residue was purified byCombiflash using hexanes-ethyl acetate as eluents to get partially purecompound 5-C (205 mg). Two partially pure compound 5-C were combined andpurified again by CombiFlash using hexanes-ethyl acetate as eluents toget compound 5-C. ¹H NMR (400 MHz, CDCl₃) δ 7.95-7.81 (m, 2H), 7.82-7.67(m, 2H), 5.26 (d, J=6.5 Hz, 1H), 4.99-4.84 (m, 1H), 2.67 (ddd, J=35.4,14.5, 8.0 Hz, 3H), 2.13-1.91 (m, 1H), 1.15 (d, J=0.9 Hz, 9H). ¹⁹F NMR(376 MHz, Chloroform-d) δ −126.81 (dt, J=170.9, 14.5 Hz, 1 F),−129.43-−130.54 (m, 0.15F), −137.42-−138.86 (m, 0.15F), −148.12 (dt,J=171.0, 4.2 Hz, 1 F), −150.85-−152.25 (m, 0.15F).

Step 3

A solution of compound 5-C (330 mg, 0.908 mmol) and hydrazine hydrate(0.18 mL, 3.7 mmol) in ethanol (10 mL) was stirred at 70° C. bath for 2hours. After being cooled to room temperature, the mixture was dilutedwith ethyl ether (30 mL) and the solids filtered off. After the filtratewas concentrated, the residue was triturated with CH₂Cl₂, and filteredoff some solids present. After the filtrate was concentrated, compound5-D was obtained. ¹H NMR (400 MHz, CDCl₃) δ 5.29-5.24 (m, 1H), 3.65-3.51(m, 1H), 2.41-2.09 (m, 4H), 1.93-1.52 (m, 2H), 1.21 (s, 9H). ¹⁹F NMR(376.1 MHz, CDCl₃) δ −124.67 (dt, J=172.1, 15.1 Hz, 1F), −126.97 (d,J=14.8 Hz, 0.1F), −129.38 (dt, J=150.2, 11.8 Hz, 0.1F), −147.22 (dt,J=172.2, 4.6 Hz, 1F), −155.11 (dd, J=149.9, 2.6 Hz, 0.1F). LCMS-ESI⁺(m/z): [M+H]⁺ calculated for C₁₁H₁₈F₂NO₂: 234.13; found: 233.9.

Step 4

A solution of compound 5-D (205 mg, 0.879 mmol) in 1 N KOH (3 mL), THF(3 mL), and water (3 mL) was stirred at 50° C. for 16 hours beforeconcentration to ˜⅓ volume. The resulting solution was cooled to 0° C.and neutralized with 1N HCl (˜3.2 mL). After the solution was dilutedwith saturated NaHCO₃ (3 mL) and THF (5 mL), the solution was stirred at0° C. and as Boc₂O (613 mg, 2.809 mmol) was added. After 2 hours,additional Boc₂O (450 mg, 2.062 mmol) was added. After 1.5 hours more at0° C., the mixture was diluted with water and extracted with ethylacetate (×2). The extracts were washed with water (×1), combined, dried(Na₂SO₄), and concentrated. The residue was purified by CombiFlash usinghexanes-ethyl acetate as eluents to get compound 5-E. ¹H NMR (400 MHz,CDCl₃) δ 5.27 (br, 1H), 4.51-4.38 (d, J=7.4 Hz, 1H), 4.17 (d, J=7.4 Hz,1H), 2.88 (br, 1H), 2.24 (m, 3H), 1.84-1.70 (m, 1H), 1.44 (s, 9H). ¹⁹FNMR (376.1 MHz, CDCl₃) δ −125.18 (d, J=172.5 Hz, 1F), −147.57 (d,J=171.8 Hz, 1F). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₁₁H₁₈F₂NO₂:234.13; found: 233.9.

Step 5

A solution of compound 5-E (173 mg, 0.694 mmol) in CH₂Cl₂ (2 mL) wasstirred at room temperature as 4 N HCl in dioxane (2 mL) was added.After 1 hour, additional 4 N HCl in dioxane (2 mL) was added and theresulting mixture was stirred at room temperature for 1 hour. Themixture was concentrated and the residue was co-evaporated with toluene(×1) before drying in high vacuum for 1 hour.

A mixture of the resulting residue, compound 5-F (285 mg, 0.691 mmol),and K₂CO₃ (191 mg, 1.382 mmol) in MeCN (2.7 mL) and AcOH (0.3 mL) wasstirred at 90° C. bath. After 2 hours, the reaction mixture was stirredat 0° C., quenched with 1 N HCl (˜4 mL), and diluted with water beforeextraction with CH₂Cl₂ (×3). The combined extracts were dried (Na₂SO₄),and concentrated. The residue was purified by preparative HPLC to get 67mg of the partially purified cyclic product.

To a solution of the partially purified cyclic product in MeCN (3 mL)was added MgBr₂ (65 mg, 0.353 mmol) and the resulting mixture wasstirred at 50° C. for 1 hour, and cooled to 0° C. before addition of 1 NHCl. After the mixture was diluted with water, the product was extractedwith CH₂Cl₂ (×3) and the combined extracts were dried (Na₂SO₄), andconcentrated. The residue was purified by preparative HPLC and theproduct containing fraction was freeze-dried to get compound 5 as a 1:1mixture with TFA. ¹H NMR (400 MHz, CDCl₃) δ 10.48 (t, J=6.0 Hz, 1H),8.49 (s, 1H), 7.43-7.29 (m, 1H), 6.91-6.73 (m, 2H), 5.80 (dd, J=9.8, 4.0Hz, 1H), 5.47 (t, J=3.6 Hz, 1H), 4.80 (s, 1H), 4.72-4.52 (m, 2H), 4.35(dd, J=13.0, 4.1 Hz, 1H), 4.09 (dd, J=12.9, 9.8 Hz, 1H), 2.50 (dd,J=14.7, 7.3 Hz, 1H), 2.40-2.29 (m, 1H), 2.11 (dq, J=13.9, 3.4 Hz, 1H),2.03-1.89 (m, 1H). ¹⁹F NMR (376.1 MHz, CDCl₃) δ −76.38 (s, 3F), −111.32(p, J=7.8 Hz, 1F), −114.54 (q, J=8.6 Hz, 1F), −117.70 (dt, J=174.1, 14.5Hz, 1F), −139.72-−142.02 (m, 1F). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated forC₂₂H₁₈F₄N₃O₅: 480.12; found: 480.2.

Example 6 Preparation of Compound 6(1aR,2R,3aS,12S,12aS)—N-(2,4-difluorobenzyl)-9-hydroxy-8,10-dioxo-1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-methanocyclopropa[e]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-7-carboxamide

Step 1

To a solution of compound 6-A (4.272 g, 30.053 mmol), PPh₃ (15.785 g,60.18 mmol), and pivaloic acid (3.5 mL, 30.446 mmol) in THF (200 m) wasstirred at 0° C. as diisopropyl azodicarboxylate (11.9 mL, 60.439 mmol)was added over 5 min. After 10 min, the mixture was warmed to roomtemperature and stirred for 30 min. The mixture was concentrated andresulting syrup was dissolved in ethyl ether. After the mixture wasfiltered and the filtrate was concentrated, the residue was purified byCombiFlash to obtain compound 6-B. 1H NMR (400 MHz, CDCl₃) δ 6.11 (s,2H), 5.80 (m, 2H), 2.29-2.11 (m, 2H),2.04 (s, 3H), 1.17 (s, 9H).

Step 1

A suspension of compound 6-B (4.875 g, 21.545 mmol) and K₂CO₃ (3.265 g,23.623 mmol) in methanol (100 mL) was stirred at room temperature for 2hours. After the reaction mixture was diluted with CH₂Cl₂ (˜150 mL), themixture was filtered and the filtrate was concentrated. The residue wastriturated with CH₂Cl₂ and the supernatant was purified by CombiFlash toobtain compound 6-C. 1H NMR (400 MHz, CDCl₃) δ 6.11 (br d, J=2H), 5.7Hz, 1H), 6.02 (br d, J=5.7 Hz, 1H), 5.82-5.72 (m, 1H), 5.14-4.98 (m,1H), 2.28-2.06 (m, 2H), 1.57 (s, 3H), 1.17 (s, 9H).

Step 3

A solution of compound 6-C (1.503 g, 8.158 mmol) in CH₂Cl₂ (50 mL) wasstirred at 0° C. as 1 M solution of ZnEt₂ in toluene (9 mL) was added.After 15 min, CH₂12 (1.45 mL, 18 mmol) followed by 1 M solution of ZnEt₂in toluene (9 mL) were added. After the mixture was stirred for 30 min,additional CH₂I₂ (1.45 mL, 18 mmol) was added. After 30 min, the mixturewas warmed to room temperature and stirred for 2 hours before additional1 M solution of ZnEt₂ in toluene (9 mL) and CH₂I₂ (1.45 mL, 18 mmol)were added. The resulting mixture was stirred at room temperature for 18hours. The reaction mixture was poured into 0° C. cold saturated NH₄Cland the product was extracted with ethyl acetate (×2). The combinedextracts were dried (Na₂SO₄), and concentrated before purification byCombiFlash to get compound 6-D. ¹H NMR (400 MHz, CDCl₃) δ 5.12 (d, J=5.2Hz, 1H), 4.78 (td, J=8.3, 4.6 Hz, 1H), 2.00-1.87 (m, 1H), 1.75-1.65 (m,1H), 1.56 (s, 1H), 1.51 (m, 1H), 1.38 (m, 1H), 1.19 (s, 9H), 0.58 (m,2H).

Step 4

A mixture of compound 6-D (1291 mg, 6.512 mmol) and PPh₃ (3794 mg, 14.47mmol) in THF (70 mL) was stirred at 0° C. bath as DIAD (2.9 mL, 14.73mmol) was added. After addition, the mixture was stirred at 0° C. for 30min and then at room temperature overnight. The mixture was concentratedto syrup and dissolved in ether (˜70 mL) and stirred at 0° C. bath for˜1 hour before filtration. After the filtrate was concentrated, theresidue was purified by CombiFlash using hexanes-ethyl acetate aseluents to obtain compound 6-E. ¹H NMR (400 MHz, Chloroform-d) δ 7.81(dd, J=5.4, 3.0 Hz, 2H), 7.70 (dd, J=5.5, 3.0 Hz, 2H), 5.15 (d, J=5.8Hz, 1H), 4.70-4.57 (m, 1H), 2.24˜2.08 (m, 2H), 1.92 (dt, J=8.6, 4.4 Hz,1H), 1.84 (d, J=16.3 Hz, 1H), 1.05 (s, 9H), 0.81 (tdd, J=8.6, 5.9, 1.3Hz, 1H), 0.11 (dt, J=6.0, 4.0 Hz, 1H).

Step 5

A solution of compound 6-E (890 mg, 2.719 mmol) and hydrazine hydrate(0.53 mL, 10.89 mmol) in ethanol (15 mL) was stirred at 70° C. bath for2 hours. After cooled to room temperature, the mixture was diluted withethyl ether (50 mL) and the resulting mixture was stirred at 0° C. bathfor 1 hour before filter the solids. After the filtrate wasconcentrated, the residue was triturated with CH₂Cl₂, and filtered offsome solids present. After the filtrate was concentrated, compound 6-Fwas obtained. ¹H NMR (400 MHz, CDCl₃) δ 5.15 (d, J=5.2 Hz, 1H), 3.33 (d,J=6.2 Hz, 1H), 1.90 (br, 2H), 1.77 (dt, J=15.8, 5.7 Hz, 1H), 1.64-1.55(m, 2H), 1.55-1.47 (m, 1H), 1.20 (s, 9H), 0.60-0.48 (m, 1H), −0.01 (dt,J=5.9, 3.8 Hz, 1H).

Step 6

A solution of compound 6-F (522 mg, 2.646 mmol) in 1 N KOH (9.1 mL), THF(9 mL), and water (9 mL) was stirred at 50° C. for 15 hours and at 70°C. for 7 hours before concentration to ˜⅓ volume. The resulting solutionwas cooled to 0° C. and neutralized with 1N HCl (˜9.2 mL). After thesolution was diluted with saturated NaHCO₃ (10 mL) and THF (10 mL), thesolution was stirred at 0° C. and as Boc₂O (1846 mg, 8.412 mmol) wasadded. After 1 hour, the mixture was warmed to room temperature andstirred for 15 hours before addition of Boc₂O (1846 mg, 8.412 mmol).After 6 hours, the mixture was diluted with water and extracted withethyl acetate (×2). The extracts were washed with water (×1), combined,dried (Na₂SO₄), and concentrated. The residue was purified by CombiFlashusing hexanes-ethyl acetate as eluents to get compound 6-G. ¹H NMR (400MHz, CDCl₃) δ 5.3 (br, 1H), 4.26 (d, J=4.4 Hz, 1H), 4.03 (d, J=6.3 Hz,1H), 2.5 (br, 1H), 1.64 (ddd, J=15.5, 6.4, 4.6 Hz, 1H), 1.59-1.49 (m,3H), 1.42 (s, 9H), 0.60-0.37 (m, 1H), −0.08 (dt, J=5.9, 3.7 Hz, 1H).

Step 7

A solution of compound 6-G (457 mg, 2.143 mmol) in CH₂Cl₂ (5.5 mL) wasstirred at room temperature as 4 N HCl in dioxane (5.5 mL) was added.After 1 hour, additional 4 N HCl in dioxane (5.5 mL) was added and theresulting mixture was stirred at room temperature for 1 hour. Themixture was concentrated and the residue was dried in high vacuumovernight.

A mixture of the resulting residue (320 mg), compound 5-F (881 mg, 2.137mmol), and K₂CO₃ (592 mg, 4.183 mmol) in MeCN (10 mL) and AcOH (1 mL)was stirred at 65° C. bath. After 3 hours, the reaction mixture wasstirred at 0° C., quenched with 1 N HCl (˜2 mL), and diluted with waterbefore extraction with CH₂Cl₂ (×3). The combined extracts were dried(Na₂SO₄), and concentrated. The residue was purified by CombiFlash (40 gcolumn) using hexanes-ethyl acetate—20% MeOH/ethyl acetate as eluents toget 433 mg of the partially purified cyclic product.

To a solution of the partially purified cyclic product in MeCN (5 mL)was added MgBr₂ (453 mg, 2.46 mmol) and MeCN (2 mL) at room temperature.The resulting mixture was stirred at 50° C. for 20 min, and cooled to 0°C. before addition of 1 N HCl. After the mixture was diluted with water,the product was extracted with CH₂Cl₂ (×3) and the combined extractswere dried (Na₂SO₄), and concentrated. The residue was purified byCombiFlash using CH₂Cl₂-20% MeOH/CH₂Cl₂ as eluents. After the combinedproduct containing fractions were concentrated, the residue wastriturated with MeCN (5 mL) for 15 min, filtered, and the solidscollected were dried in vacuum to obtain compound 6. ¹H NMR (400 MHz,CDCl₃) δ 10.51 (t, J=6.0 Hz, 1H), 8.47 (s, 1H), 7.40-7.29 (m, 1H), ˜7(br, 1H), 6.90-6.76 (m, 2H), 5.94 (dd, J=9.8, 4.0 Hz, 1H), 5.21 (d,J=3.8 Hz, 1H), 4.63 (dd, J=5.9, 2.7 Hz, 2H), 4.61-4.53 (m, 1H), 4.32(dd, J=13.0, 4.1 Hz, 1H), 4.04 (dd, J=12.9, 9.9 Hz, 1H), 1.86-1.64 (m,2H), 1.61 (p, J=4.0 Hz, 1H), 1.52 (dt, J=13.6, 3.4 Hz, 1H), 0.87 (q,J=7.5 Hz, 1H), 0.60 (dt, J=6.7, 3.4 Hz, 1H). ¹⁹F NMR (376.1 MHz, CDCl₃)δ −76.43 (s, 3F), −111.61 (p, J=7.7 Hz, 1F), −114.58 (q, J=8.5 Hz, 1F).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₂H₂₀F₂N₃O₅: 444.14; found:444.2.

Example 7 Preparation of Compound 7(1aS,2S,3aR,12R,12aR)—N-(2,4-difluorobenzyl)-9-hydroxy-8,10-dioxo-1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-methanocyclopropa[e]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-7-carboxamide

Step 1

A 500-mL 1-neck round bottom flask was charged with reactant 7-A (5.0 g,35 mmol) and DCM (100 ml). The reaction mixture was cooled to 0° C. withstirring. 1 N diethylzinc in hexane (39 ml) was added to the reactionmixture slowly. The reaction mixture was stirred at 0° C. for 15minutes. Diiodomethane (4.25 mL) was added followed by 1N diethylzinc inhexane (39 mL). After stirring another 15 minutes, additionaldiiodomethane (4.25 ml) was added to the reaction mixture. Then thereaction mixture was warmed to room temperature and stirred forovernight. The reaction mixture was poured onto a cold aqueous solutionof NH₄Cl and extracted with ethyl acetate. The organic layer was driedand evaporated in vacuo. The residue was purified by columnchromatography on silica gel with hexane-EtOAc to afford 7-B. ¹H NMR(400 MHz, Chloroform-d) δ 5.34-5.02 (m, 1H), 4.45 (ddd, J=8.7, 7.7, 4.7Hz, 1H), 2.31 (dt, J=13.4, 7.8 Hz, 1H), 2.02 (s, 3H), 1.84-1.59 (m, 2H),1.25-1.07 (m, 2H), 0.92 (dt, J=5.4, 3.9 Hz, 1H), 0.54 (td, J=7.7, 5.5Hz, 1H).

Step 2

A 500-mL 1-neck round bottom flask was charged with reactant 7-B (5.5 g,35 mmol), triphenylphosphine (20.3 g, 77 mmol), phthalimide (8.3 g, 56mmol) and THF (200 ml). The reaction mixture was cooled to 0° C. withstirring. Diisopropyl azodicarboxylate (DIAD) (15.3 ml, 77 mmol) wasadded to the reaction mixture slowly. The reaction mixture was stirredat room temperature overnight. The reaction mixture was concentrateddown, re-dissolved in ether and stirred at 0° C. for 10 minutes. Solid(triphenylphosphine oxide) was filtered away. The filtrate wasconcentrated and purified by column chromatography on silica gel withhexane-EtOAc to obtain 7-C. ¹H NMR (400 MHz, Acetonitrile-d3) δ8.06-7.61 (m, 4H), 5.84 (d, J=5.1 Hz, 1H), 4.88-4.50 (m, 1H), 2.29 (dd,J=15.1, 8.7 Hz, 1H), 2.01 (s, 3 H), 1.98 (m, 1H), 1.94 (d, J=2.4 Hz,1H), 1.49 (m, 1H), 0.68 (td, J=8.2, 5.5 Hz, 1H), 0.56 (s, 1H).

Steps 3 and 4

A 250-mL 1-neck round bottom flask was charged with reactant 7-C (1.0 g,3.5 mmol), hydrazine monohydrate (˜2 ml) and EtOH (20 ml). The reactionmixture was stirred at 70° C. for 30 minutes. The reaction mixture wasconcentrated under high vacuum for 1 hour to afford 7-D. The crudereaction mixture was re-dissolved in THF (20 mL). Saturated NaHCO₃ (20mL) and di-tert-butyl dicarbonate (8 g, 36.7 mmol) were added and thereaction mixture was stirred over 24 hours. The reaction mixture wasextracted with EtOAc (2×100 mL) and dried over Na₂SO₄. Afterconcentration, the crude was purified by column chromatography on silicagel with hexane-EtOAc to obtain 7-E. ¹H NMR (400 MHz, Chloroform-d) δ4.63 (td, J=8.3, 4.6 Hz, 1H), 4.01-3.81 (m, 1H), 2.17 (s, 1H), 1.81 (dd,J=14.4, 7.8 Hz, 1H), 1.55 (ddt, J=8.0, 5.6, 4.2 Hz, 1H), 1.39 (s, 9H),1.38-1.31 (m, 2H), 0.68-0.33 (m, 2H).

Step 5

A 100-mL 1-neck round bottom flask was charged with reactant 7-E (0.5 g,2.34 mmol), triphenylphosphine (1.35 g, 5.1 mmol), benzoic acid (0.46 g,3.8 m mol) and THF (20 ml). The reaction mixture was cooled to 0° C.with stirring. DIAD (1.01 ml, 5.1 mmol) was added to the reactionmixture slowly. The reaction mixture was stirred at room temperature forovernight. The reaction mixture was concentrated down, re-dissolved inether and stirred at 0° C. for 10 minutes. Solid (triphenylphosphineoxide) was filtered away. The crude was purified was purified by columnchromatography on silica gel with hexane-EtOAc to obtain 7-F. ¹H NMR(400 MHz, Chloroform-d) δ 8.16-7.77 (m, 2H), 7.58 (dd, J=7.1, 1.6 Hz,1H), 7.54-7.36 (m, 2H), 4.99-4.76 (m, 1H), 4.02 (dt, J=8.7, 3.2 Hz, 1H),1.70 (d, J=3.3 Hz, 1H), 1.62 (ddd, J=8.7, 5.1, 3.6 Hz, 1H), 1.53-1.44(m, 1H), 1.30 (s, 9H), 0.96 (dd, J=6.3, 2.6 Hz, 2H), 0.63-0.47 (m, 1H),0.00 (dd, J=6.3, 3.4 Hz, 1H).

Step 6

A 100-mL 1-neck round bottom flask was charged with 7-F (0.7 g, 2.2mmol), THF (10 mL) and MeOH (5 mL). 1 N KOH (4.4 mL) was added to thereaction mixture. The reaction mixture was stirred at room temperaturefor 30 minutes. After acidification with 1 N HCl to pH=4, the reactionmixture was extracted with EtOAc (2×50 ml). The combined organic layerswere dried by Na₂SO₄. After concentration, the crude was purified bycolumn chromatography on silica gel with hexane-EtOAc to obtain the Bocprotected product. The Boc protected product in DCM was stirred at roomtemperature as 5.5 mL of 4 N HCl in dioxane was added in. After stirredat room temperature for 2 hours, the reaction mixture was concentratedand the residue was dried under high vacuum for overnight. The resulting7-G was used for the next reaction without further purification.

Step 7

A 100-mL 1-neck round bottom flask was charged with 7-G (0.22 g, 1.47mmol), H (0.60 g, 1.47 mmol), potassium carbonate (0.40 g, 2.90 mmol),acetic acid (0.71 g, 11.83 mmol) and acetonitrile (10 mL). The reactionmixture was stirred at 65° C. bath for 2 hours. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc (100 mL),washed with saturated NaHCO₃ and dried over Na₂SO₄. After concentration,the crude was purified by column chromatography on silica gel withhexane-EtOAc to obtain 7-I. [M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₅: 458;found: 458.

Step 8

A 50-mL 1-neck round bottom flask was charged with 7-I (0.20 g, 0.44mmol), magnesium bromide (0.21 g, 1.14 mmol) and acetonitrile (5 mL).The resulting mixture was stirred at 50° C. for 10 minutes. Then themixture was stirred at 0° C. bath and 1 N HCl (˜4 mL) was added,followed by addition of water (˜5 mL). The solid was filtered and washedwith water. After drying under high vacuum overnight, compound 7 wasobtained. ¹H NMR (400 MHz, Chloroform-d) δ 12.33 (s, 1H), 10.36 (s, 1H),8.29 (s, 1H), 7.44-7.30 (m, 1H), 6.89-6.66 (m, 2H), 5.89 (d, J=10.0 Hz,1H), 5.25-5.13 (m, 1H), 4.75-4.43 (m, 3H), 4.20 (s, 1H), 4.10-3.84 (m,1H), 1.90-1.30 (m, 4H), 0.86 (t, J=7.5 Hz, 1H), 0.58 (dd, J=6.6, 3.3 Hz,1H). 1F NMR (376 MHz, Chloroform-d) δ −112.30, −114.74. [M+H]⁺calculated for C₂₁H₂₀F₂N₃O₅: 444; found: 444.

Example 8 Preparation of Compound 8(1aS,2S,10aS,11R,11aR)—N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1a,2,4,6,10,10a,11,11a-octahydro-1H-2,11-methanocyclopropa[4,5]pyrido[1,2-a]pyrido[1,2-d]pyrazine-7-carboxamide

Step 1

A mixture of the compound 8-A (1.002 g, 3.894 mmol) and Pd(OAc)₂ (15.0mg, 0.067 mmol) in ether (15 mL) was stirred at 0° C. as diazomethane inether (10 mL) was added over ˜3 min. After 30 min at 0° C., additionaldiazomethane in ether (10 mL) was added and the mixture was stirred at0° C. for 30 min. The mixture was filtered through celite pad andconcentrated. The residue was purified by Combiflash (40 g column) usinghexanes-ethyl acetate as eluents to provide compound 8-B. ¹H NMR (400MHz, Chloroform-d) δ 7.35-7.28 (m, 2H), 7.26-7.21 (m, 2H), 7.21-7.14 (m,1H), 3.82 (d, J=1.8 Hz, 1H), 3.78 (q, J=6.7 Hz, 1H), 3.28 (s, 3H), 2.64(s, 1H), 2.44 (d, J=2.0 Hz, 1H), 1.63 (d, J=11.1 Hz, 1H), 1.48 (m, 1H),1.46 (d, J=6.5 Hz, 3H), 1.08 (d, J=11.1 Hz, 1H), 1.01 (t, J=6.9 Hz, 1H),0.54 (dt, J=6.1, 3.0 Hz, 1H), 0.18 (q, J=7.0 Hz, 1H). LCMS-ESI⁺ (m/z):[M+H]⁺ calculated for C₁₇H₂₂NO₂: 272.17; found: 272.1.

Step 2

A mixture of compound 8-B (3720 mg, 11.7 mmol) and 10% Pd/C (711 mg) inEtOH (60 mL) was stirred under H₂ atmosphere. After 20 hours, themixture was filtered through celite and the filtrate was concentrated,and the residue was used for the Boc protection. LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₉H₁₄NO₂: 168.10; found: 168.0.

The residue was stirred in THF (50 mL) at room temperature as Boc₂O(6.00 g, 27.49 mmol) and DIEA (6 mL, 34.45 mmol) were added. After ˜30min, the reaction mixture was concentrated to ˜⅓ volume, diluted withethyl acetate, and washed with water (twice). After the aqueousfractions were extracted with ethyl acetate, the organic fractions werecombined, dried (Na2SO4) and concentrated. The residue was purified byCombiFlash (120 g column) using hexanes-ethyl acetate as eluents toobtain compound 8-C. ¹H NMR (400 MHz, Chloroform-d) δ 4.39 (s, 0.5H),4.25 (s, 0.5H), 3.86 (s, 0.5H), 3.77 (s, 0.5H), 3.73 (s, 1.5H), 3.71 (s,1.5H), 2.74 (m, 1H), 1.48 (s, 4.5H), 1.44-1.42 (m, 1H), 1.41 (s, 4.5H),1.36-1.21 (m, 1H), 1.06 (m, 2H), 0.50 (dt, J=5.9, 3.0 Hz, 1H), 0.27 (qd,J=7.2, 2.8 Hz, 1H). LCMS-ESI+(m/z): [M+H]+ calculated for C₁₄H₂₂NO₄:268.15; found: 267.7.

Step 3

A solution of compound 8-C (400 mg, 1.496 mmol) in THF (3 mL) wasstirred at 0° C. as 2.0 M LiBH₄ in THF (1.5 mL) was added. After 5 min,the mixture was stirred at room temperature. After 66 hours, thereaction mixture was diluted with ethyl acetate and added water slowly.After two phases were separated, the aqueous fraction was extracted withethyl acetate and the two organic fractions were washed with water,combined, dried (Na₂SO₄), and concentrated. The residue was purified byCombiFlash (40 g column) using hexanes-ethyl acetate as eluents to yieldcompound 8-D. ¹H NMR (400 MHz, Chloroform-d) δ 4.14 (dd, J=2.3, 1.3 Hz,1H), 3.68-3.53 (m, 2H), 3.50-3.41 (m, 1H), 2.61 (s, 1H), 2.39 (d, J=2.1Hz, 1H), 1.49 (s, 9H), 1.30 (td, J=6.8, 6.2, 2.3 Hz, 1H), 1.16 (dt,J=11.1, 1.8 Hz, 1H), 1.10-1.03 (m, 1H), 0.99 (td, J=7.0, 3.0 Hz, 1H),0.46 (dt, J=6.5, 3.2 Hz, 1H), 0.22 (q, J=7.1 Hz, 1H). LCMS-ESI⁺ (m/z):[M+H]⁺ calculated for C₁₃H₂₂NO₃: 240.16; found: 239.7.

Step 4

A solution of compound 8-D (345 mg, 1.442 mmol), phthalimide (351 mg,2.386 mmol), and PPh₃ (852 mg, 3.248 mmol) in THF (20 mL) was stirred at0° C. as DIAD (0.65 mL, 3.301 mmol) was added. After addition, themixture was stirred at 0° C. for 30 min and then at rt. After 16 hours,the solution was concentrated to syrup and the residue was stirred inether (50 mL) at 0° C. for 1.5 hours before filtration. The filtrate wasconcentrated, and the residue was purified using CombiFlash (40 gcolumn) with hexane-ethyl acetate as eluents to obtain compound 8-E. 1HNMR (400 MHz, Chloroform-d) δ 7.84 (ddt, J=10.3, 7.8, 3.8 Hz, 2H),7.78-7.61 (m, 2H), 4.23 (s, 0.5H), 4.11 (m, 0.5H), 3.99 (dd, J=13.1, 4.1Hz, 0.5H), 3.88 (dd, J=12.7, 6.7 Hz, 0.5H), 3.73-3.43 (m, 2H), 2.41 (d,J=2.1 Hz, 1H), 1.49 (s, 4.5H), 1.49-1.2 (m, 2H), 1.31 (s, 4.5H), 1.09(d, J=11.5 Hz, 1H), 0.94-0.86 (m, 0.5H), 0.85-0.77 (m, 0.5H), 0.44 (m,1H), 0.17 (m, 1H). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₂₅N₂O₄:369.18; found: 368.9.

Step 5 and Step 6 To a solution of compound 8-E (516 mg, 1.401 mmol) inEtOH (30 mL) was added hydrazine hydrate (0.29 mL) at rt and theresulting solution was stirred at 70° C. After 4.5 hours, the mixturewas cooled to room temperature and diluted with ethyl ether (30 mL) andstirred at 0° C. for 30 min before filtration. The filtrate wasconcentrated and the residue was dissolved in CH₂Cl₂ before filtrationto remove some insoluble material. The resulting filtrate wasconcentrated to obtain crude compound 8-F. LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₁₃H₂₃N₂O₂: 239.18; found: 238.9.

The mixture of crude compound 8-F, compound 8-G (341 mg, 1.408 mmol),and NaHCO₃ (240 mg, 2.857 mmol) in water (4 mL) and EtOH (4 mL) wasstirred at rt. After 15 hours, the mixture was diluted with water andextracted with ethyl acetate (twice). The extracts were washed withwater, combined, dried (Na₂SO₄), concentrated. To the crude residue inCH₂Cl₂ (5 mL) was added 4 N HCl in dioxane (10 mL) at room temperatureand the resulting mixture was stirred at room temperature for 2 hours.The mixture was concentrated, co-evaporated with toluene, and driedunder vacuum for 30 min.

A suspension of the residue and DBU (1.06 mL, 7.088 mmol) in toluene (10mL) was stirred at 110° C. bath. After 30 min, the mixture wasconcentrated and the residue was dissolved in CH₂Cl₂ (˜50 mL) and washedwith aqueous NH₄Cl (twice). After the aqueous fractions were extractedwith CH₂Cl₂ (twice), the three organic fractions were combined, dried(Na₂SO₄), and concentrated. The residue was purified by CombiFlash (24 gcolumn) using ethyl acetate—20% MeOH/ethyl acetate as eluents to obtaincompound 8-H. ¹H NMR (400 MHz, Chloroform-d) δ 8.17 (s, 1H), 5.04 (s,1H), 4.09 (s, 1H), 4.08 (s, 3H), 3.91 (s, 3H), 3.86-3.71 (m, 2H), 2.73(d, J=1.8 Hz, 1H), 1.43-1.21 (m, 2H), 1.13 (d, J=12.1 Hz, 2H), 0.60 (dt,J=6.7, 3.1 Hz, 1H), 0.40 (q, J=7.3 Hz, 1H). LCMS-ESI⁺ (m/z): [M+H]⁺calculated for C₁₇H₁₉N₂O₅: 331.13; found: 331.2.

Step 7

A mixture of compound 8-H (40 mg, 0.121 mmol) in THF (1 mL) and MeOH (1mL) was stirred at room temperature as 1 N KOH (1 mL) was added. After30 min, the reaction mixture was acidified with 1 N HCl (˜1.1 mL),concentrated to ˜2 mL, and diluted with brine before extraction withCH₂Cl₂ (×3). The combined extracts was dried (Na₂SO₄) and concentrated.

To the solution of crude acid were added 2,4-difluorobenzylamine (26 mg,0.182 mmol), and HATU (56 mg, 0.147 mmol) at room temperature followedby DIEA (0.32 mL, 1.835 mmol). After 1 hour, additional2,4-difluorobenzylamine (26 mg, 0.182 mmol) and HATU (56 mg, 0.147 mmol)were added. After 1 hour, the reaction mixture was diluted with waterand the product was extracted with CH₂Cl₂ (×2). The extracts were washedwith water, combined, dried (Na₂SO₄) and concentrated.

The residue was purified by CombiFlash (24 g column) using ethylacetate-20% MeOH/ethyl acetate as eluents to obtain compound 8-I. ¹H NMR(400 MHz, Chloroform-d) δ 10.44 (t, J=6.0 Hz, 1H), 8.36 (s, 1H), 7.34(td, J=8.6, 6.8 Hz, 1H), 6.87-6.69 (m, 2H), 5.02 (s, 1H), 4.60 (qd,J=15.2, 5.9 Hz, 2H), 4.16-4.07 (m, 1H), 4.04 (s, 3H), 3.83 (t, J=12.0Hz, 1H), 3.76 (dd, J=12.2, 2.7 Hz, 1H), 2.72 (d, J=1.7 Hz, 1H),1.39-1.21 (m, 2H), 1.18-1.07 (m, 2H), 0.59 (dt, J=6.6, 3.2 Hz, 1H), 0.39(q, J=7.3 Hz, 1H). ¹⁹F NMR (376 MHz, Chloroform-d) δ −112.08 (p, J=7.7Hz), −114.77 (q, J=8.6 Hz). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated forC₂₃H₂₂F₂N₃O₄: 442.16; found: 442.3.

Step 8

A suspension of compound 8-I (47 mg, 0.106 mmol) in MeCN (2 mL) wasstirred at 50° C. as MgBr₂ (49 mg, 0.266 mmol) was added. After 30 min,the reaction mixture was stirred at 0° C. and added 1 N HCl to make themixture a solution (˜2 mL). After the mixture was diluted with CH₂Cl₂and water, two fractions were separated and the aqueous fraction wasextracted with CH₂Cl₂ (twice). The combined organic fractions were dried(Na₂SO₄) and concentrated. The residue was purified by CombiFlash (24 gcolumn) using CH₂Cl₂ and 20% MeOH in CH₂Cl₂ as eluents to obtaincompound 8. The residue was triturated in MeCN at 0° C. for 30 min andfiltered. The collected solids were dried in vacuum to obtain additionalcompound 8. ¹H NMR (400 MHz, Chloroform-d) δ 11.68 (s, 1H), 10.43 (s,1H), 8.28 (s, 1H), 7.36 (td, J=8.6, 6.4 Hz, 1H), 6.86-6.75 (m, 2H), 4.96(s, 1H), 4.64 (d, J=6.0 Hz, 2H), 4.12 (d, J=7.9 Hz, 1H), 3.81 (d, J=7.6Hz, 2H), 2.79 (d, J=1.7 Hz, 1H), 1.42 (d, J=11.0 Hz, 2H), 1.17 (d,J=12.3 Hz, 2H), 0.65 (dt, J=6.7, 3.2 Hz, 1H), 0.46 (q, J=7.3 Hz, 1H).¹⁹F NMR (376 MHz, Chloroform-d) δ −112.36 (p, J=7.5 Hz), −114.76 (q,J=8.6 Hz). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₂H₂₀F₂N₃O₄: 428.14;found: 428.3.

Example 9 Preparation of Compound 9(1aS,2S,10aS,11R,11aR)-5-hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,4,6,10,10a,11,11a-octahydro-1H-2,11-methanocyclopropa[4,5]pyrido[1,2-a]pyrido[1,2-d]pyrazine-7-carboxamide

Step 1

A mixture of compound 8-H (84 mg, 0.254 mmol) in THF (2 mL) and MeOH (2mL) was stirred at room temperature as 1 N KOH (1 mL) was added. After30 min, the reaction mixture was concentrated to ˜2 mL, acidified with 1N HCl (˜1.1 mL), concentrated to ˜2 mL, and diluted with brine beforeextraction with CH₂Cl₂ (thrice). The combined extracts was dried(Na₂SO₄) and the solution was used for the next reaction.

To the crude acid solution were added 2,4,6-trifluorobenzylamine (57 mg,0.354 mmol), and HATU (157 mg, 0.413 mmol) at room temperature followedby DIEA (0.31 mL, 1.780 mmol). After ˜30 min, additional DIEA (0.31 mL,1.78 mmol) was added. After 1 hour, the reaction mixture was washed withsaturated NH₄Cl and water. After the aqueous fractions were extractedwith CH₂Cl₂, the two organic fractions were combined, dried (Na₂SO₄) andconcentrated. The residue was purified by CombiFlash (24 g column) usingethyl acetate—20% MeOH/ethyl acetate as eluents to obtain compound 9-A.¹H NMR (400 MHz, Chloroform-d) δ 10.37 (t, J=5.7 Hz, 1H), 8.36 (s, 1H),6.74-6.57 (m, 2H), 5.03 (s, 1H), 4.64 (qd, J=14.5, 5.7 Hz, 2H),4.11-4.06 (m, 1H), 4.04 (s, 3H), 3.83 (t, J=12.0 Hz, 1H), 3.76 (dd,J=12.2, 2.8 Hz, 1H), 2.74 (d, J=1.8 Hz, 1H), 1.33 (dd, J=13.7, 2.8 Hz,2H), 1.19-1.08 (m, 2H), 0.60 (dt, J=6.6, 3.1 Hz, 1H), 0.40 (q, J=7.2 Hz,1H). ¹⁹F NMR (376 MHz, Chloroform-d) δ −108.39-−109.90 (m, 1F), −111.99(t, J=6.9 Hz, 2F). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₃H₂₁F₃N₃O₄:460.15; found: 460.3.

Step 2

A suspension of compound 9-A (106 mg, 0.231 mmol) in MeCN (4 mL) wasstirred at 50° C. and MgBr₂ (107 mg, 0.581 mmol) was added. After 30min, the reaction mixture was stirred at 0° C. and 1 N HCl was added toobtain a solution (˜2 mL) After the mixture was diluted with CH₂Cl₂ andwater, two fractions were separated and the aqueous fraction wasextracted with CH₂Cl₂ (twice). The combined organic fractions were dried(Na₂SO₄) and concentrated. The residue was purified by CombiFlash (12 gcolumn) using CH₂Cl₂ and 20% MeOH in CH₂Cl₂ as eluents to get 85 mg ofcompound 12. The residue was triturated in MeCN at 0° C. for 30 min andfiltered. The collected solids were dried in vacuum to obtain compound9. ¹H NMR (400 MHz, Chloroform-d) δ 10.35 (s, 1H), 8.27 (s, 1H), 6.65(dd, J=8.7, 7.6 Hz, 2H), 4.96 (s, 1H), 4.66 (dd, J=5.7, 4.0 Hz, 2H),4.09 (d, J=8.3 Hz, 1H), 3.80 (d, J=8.1 Hz, 2H), 2.79 (s, 1H), 1.41 (d,J=11.1 Hz, 2H), 1.18 (t, J=10.6 Hz, 2H), 0.65 (dt, J=6.8, 3.2 Hz, 1H),0.46 (q, J=7.3 Hz, 1H). ¹⁹F NMR (376 MHz, Chloroform-d) δ−109.13-−109.32 (m, 1F), −111.99 (t, J=7.0 Hz, 2F). LCMS-ESI⁺ (m/z):[M+H]⁺ calculated for C₂₂H₁₉F₃N₃O₄: 446.13; found: 446.3.

Example 10 Preparation of Compound 10(1aS,2S,3aR,12R,12aR)-9-hydroxy-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,3a,4,8,10,12,12a-octahydro-1H-2,12-methanocyclopropa[e]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-7-carboxamide

Step 1

A 100-mL 1-neck round bottom flask was charged with 7-G (0.26 g, 1.74mmol), 10-A (0.8 g, 1.74 mmol), potassium carbonate (0.97 g, 7.03 mmol),acetic acid (2.55 g, 42.5 mmol) and acetonitrile (30 mL). The reactionmixture was stirred at 65° C. for 2 hours. After cooled back to roomtemperature, the reaction mixture was diluted with EtOAc (100 mL),washed with sat NaHCO₃ and dried over Na₂SO₄. After concentration, thecrude was purified by column chromatography on silica gel withhexane-EtOAc to obtain 10-B. [M+H]⁺ calculated for C₂₁H₂₀F₂N₃O₅: 476;found: 476.

Step 2

A 50-mL 1-neck round bottom flask was charged with 10-B (0.30 g, 0.63mmol), magnesium bromide (0.30 g, 1.63 mmol) and acetonitrile (5 mL).The resulting mixture was stirred at 50° C. for 10 minutes. Then themixture was stirred at 0° C. while 1 N HCl (˜4 mL) was added. Additionalwater (˜5 mL) was added to wash down solids forming on the flask walls.The resulting solid was filtrated and washed with water. After dryingunder high vacuum overnight, Compound 10 was obtained. ¹H NMR (400 MHz,Chloroform-d) δ 12.31 (s, 1H), 10.32 (s, 1H), 8.31 (s, 1H), 6.83-6.54(m, 2H), 5.90 (d, J=9.2 Hz, 1H), 5.22 (d, J=3.9 Hz, 1H), 4.79-4.47 (m,4H), 4.22 (s, 1H), 4.08-3.86 (m, 1H), 1.92-1.64 (m, 2H), 1.65-1.43 (m,2H), 0.86 (q, J=7.4 Hz, 1H), 0.59 (dt, J=6.6, 3.2 Hz, 1H). ¹⁹F NMR (376MHz, Chloroform-d) δ −109.17, −111.95. [M+H]⁺ calculated forC₂₁H₂₀F₂N₃O₅: 462; found: 462.

Example 11 Preparation of Compound 11(1aR,2R,10aR,11S,11aS)-5-hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,4,6,10,10a,11,11a-octahydro-1H-2,11-methanocyclopropa[4,5]pyrido[1,2-a]pyrido[1,2-d]pyrazine-7-carboxamide

Step 1

A suspension of compound 11-A (965 mg, 3.061 mmol),2,4,6-trifluorobenzylamine (493 mg, 3.06 mmol), and HATU (1402 mg, 3.688mmol) in CH₂Cl₂ (15 mL) was stirred in 0 OC as DIEA (2 mL, 11.48 mmol)was added.

After 1.5 hours at 0° C., the reaction mixture was diluted with ethylacetate, and washed with water (twice). After the aqueous fractions wereextracted with ethyl acetate, the organic fractions were combined, dried(Na₂SO₄), and concentrated. The residue was purified by CombiFlash (40 gcolumn) using hexanes-ethyl acetate as eluents to obtain compound 11-B.¹H NMR (400 MHz, Chloroform-d) δ 10.30 (t, J=5.9 Hz, 1H), 8.40 (s, 1H),6.79-6.51 (m, 2H), 4.65 (d, J=5.6 Hz, 2H), 4.48 (t, J=4.8 Hz, 1H), 4.01(d, J=4.8 Hz, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.38 (s, 6H). ¹⁹F NMR(376 MHz, Chloroform-d) δ −109.07-−109.35 (m, 1F), −111.93 (t, J=6.9 Hz,2F). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₀H₂₂F₃N₂O₇: 459.14; found:459.2.

Step 2

A mixture of the compound 11-B (300 mg, 0.654 mmol) and methanesulfonicacid (63 mg, 0.655 mmol) in MeCN (3 mL) and acetic acid (0.3 mL) washeated to 75° C. for 2 hours. After cooling the solution, aminoalcohol11-D (98 mg, 0.655 mmol), and K₂CO₃ (272 mg, 1.968 mmol) were added andthe mixture was diluted with MeCN (10 mL) and stirred at 65° C. for 21hours. The reaction mixture was concentrated to remove most of MeCN,diluted with water (˜30 mL) and extracted with ethyl acetate (˜30 mL,twice). The extracts were washed with water, combined, dried (Na₂SO₄),and concentrated. The residue was purified by CombiFlash (40 g column)using hexanes-ethyl acetate as eluents to obtain compound 11-E. ¹H NMR(400 MHz, Chloroform-d) δ 10.27 (t, J=5.7 Hz, 1H), 8.37 (s, 1H),6.73-6.56 (m, 2H), 5.81 (dd, J=9.9, 3.8 Hz, 1H), 5.25 (d, J=3.9 Hz, 1H),4.71-4.57 (m, 2H), 4.53-4.48 (m, 1H), 4.21 (dd, J=12.8, 3.8 Hz, 1H),4.02 (s, 3H), 3.98 (dd, J=12.7, 9.9 Hz, 1H), 1.67 (dt, J=13.5, 1.1 Hz,2H), 1.54 (ddd, J=7.5, 5.4, 3.6 Hz, 1H), 1.48 (dt, J=13.5, 3.4 Hz, 1H),0.79 (td, J=8.0, 6.7 Hz, 1H), 0.54 (dt, J=6.7, 3.4 Hz, 1H). ¹⁹F NMR (376MHz, Chloroform-d) δ −108.89-−109.13 (m, 1F), −111.96 (t, J=7.0 Hz, 2F).LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₃H₂₁F₃N₃O₅: 476.14; found:476.3.

Step 3

A suspension of compound 11-E (151 mg, 0.318 mmol) in MeCN (4 mL) wasstirred at 50° C. and MgBr₂ (146 mg, 0.793 mmol) was added. After 30min, the reaction mixture was stirred at 0° C. 1 N HCl and was added toobtain a solution (˜2 mL). The solution was diluted with water, and theproduct was extracted with CH₂Cl₂ (thrice). The combined organicextracts were dried (Na₂SO₄) and concentrated. The residue was purifiedby CombiFlash (24 g column) using CH₂Cl₂ and 20% MeOH in CH₂Cl₂ aseluents, then further purified by trituration in MeOH (˜2 mL). After themixture was stored in the freezer, the solids were filtered and washedwith MeOH. The collected solids were dried in vacuum to obtain compound11. ¹H NMR (400 MHz, Chloroform-d) δ 12.28 (s, 1H), 10.29 (t, J=5.7 Hz,1H), 8.27 (s, 1H), 6.72-6.58 (m, 2H), 5.89 (dd, J=9.8, 4.1 Hz, 1H), 5.22(d, J=3.9 Hz, 1H), 4.73-4.59 (m, 2H), 4.59-4.54 (m, 1H), 4.19 (dd,J=12.8, 4.1 Hz, 1H), 3.99 (ddd, J=12.7, 9.9, 0.7 Hz, 1H), 1.79-1.74 (m,1H), 1.72 (d, J=13.5 Hz, 1H), 1.63-1.59 (m, 1H), 1.51 (dt, J=13.6, 3.5Hz, 1H), 0.90-0.81 (m, 1H), 0.59 (dt, J=6.7, 3.4 Hz, 1H). ¹⁹F NMR (376MHz, Chloroform-d) δ −109.21 (tt, J=8.8, 6.3 Hz, 1F), −111.98 (t, J=6.9Hz, 2F). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₂H₁₉F₃N₃O₅: 462.13;found: 462.3.

Example 12 Preparation of Compound 12(1aR,2R,10aR,11S,11aS)-5-hydroxy-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-1a,2,4,6,10,10a,11,11a-octahydro-1H-2,11-methanocyclopropa[4,5]pyrido[1,2-a]pyrido[1,2-d]pyrazine-7-carboxamide

Step 1

2,2-dihydroxyacetic acid (12-A) in MeOH was refluxed for 24 h. After thereaction was cooled to room temperature and concentrated under vacuum,it was diluted with DCM (25 mL) and concentrated again to provide methyl2-hydroxy-2-methoxyacetate (12-B).

1H NMR (400 MHz, Chloroform-d) δ 4.86 (s, 1H), 3.82 (s, 3H), 3.48 (s,3H).

Step 2

A solution of Compound 12-B in toluene was cooled to 0° C. under N₂.L(−)-alpha-Methylbenzylamine, 99+%, (99% ee) was added via syringeslowly. The reaction was warmed to room temperature and stirred for 1.5hours. The presence of the starting material was monitored by thin layerchromatography (TLC).

The reaction was quenched with water and the aqueous and organic layersseparated. The aqueous layer was extracted with EtOAc. The organiclayers were combined and washed with brine, dried (Na₂SO₄), andconcentrated to provide compound 12-C.

Step 3

A solution of compound 12-C in N, N-dimethylformamide was cooled to −15°C. under N₂. TFA was added via syringe slowly over 15 min. Afterstirring for 10 min, freshly cracked cyclopentadiene (6.76 g, 0.102 mol)was added via syringe over 10 min. The reaction was stirred for 1.5hours at −15 to −100C and monitored via TLC and LCMS.

The reaction mixture was diluted with heptane (100 mL), quenched withsaturated aqueous Na₂CO₃, and stirred for 10 min. The layers wereseparated, the organic layer was washed with brine, dried (MgSO₄), andconcentrated. The crude mixture was purified from the organic layer byCombiFlash on silica gel with 0-50% EtOAc/Hexane to obtain compound12-D.

¹H NMR (400 MHz, Chloroform-d) δ 7.32-7.11 (m, 5H), 6.42 (ddd, J=5.6,3.1, 1.3 Hz, 1H), 6.27 (dd, J=5.6, 1.9 Hz, 1H), 4.31 (q, J=1.6 Hz, 1H),3.35 (s, 3H), 3.03 (q, J=6.5 Hz, 1H), 2.93-2.88 (m, 1H), 2.22 (s, 1H),1.42 (t, J=5.8 Hz, 4H).

Step 4

The mixture of 12-D (1.77 g, 6.878 mmol) and Pd(OAc)₂ (31 mg, 0.138mmol) in ether (30 mL) was stirred at 0° C. as diazomethane in ether(freshly made) (10 mL) was added slowly. After the addition, the mixturewas stirred for ˜30 min and TLC indicated a mixture of the startingmaterial and the product. Additional diazomethane was added every 30 minuntil no starting material was detected via TLC. The reaction wasquenched with AcOH (5 mL) at 0° C. and stirred for about 20 min,concentrated, and purified by Combiflash using silica gel column withHexanes-EtOAc as eluent to obtain compound 12-E.

¹H NMR (400 MHz, Chloroform-d) δ 7.36-7.10 (m, 5H), 3.88-3.67 (m, 2H),3.26 (s, 3H), 2.63 (s, 1H), 2.47-2.36 (m, 1H), 1.68-1.54 (m, 1H), 1.45(d, J=6.5 Hz, 4H), 1.13-0.94 (m, 2H), 0.54 (dt, J=6.2, 3.1 Hz, 1H), 0.17(q, J=7.1 Hz, 1H).

Step 5

The mixture of compound 12-E (1 g, 3.7 mmol) and 10% Pd/C (1 g) in EtOH(150 mL) was stirred under H₂ atmosphere for 36 hours. The reactionmixture was filtered through Celite and the filtrate was concentrated.

The residue obtained from the above hydrogenation was stirred in THF (20mL) at room temperature as Boc₂O (1.7 g, 7.7 mmol) and DIPEA (2 mL, 11.6mmol) were added and allowed to continue for one hour. The reactionmixture was concentrated, and the resulting residue was purified byCombiFlash on silica gel column using hexanes—EtOAc as eluents to obtaincompound 12-F. LCMS: m/z=267.6.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for Chemical Formula: C14H21NO4,Molecular Weight: 267.32; found: 267.67.

¹H NMR (400 MHz, Chloroform-d) δ 4.32 (dd, J=55.7, 2.2 Hz, 1H), 3.82 (d,J=43.3 Hz, 1H), 3.72 (d, J=3.6 Hz, 3H), 2.78-2.68 (m, 1H), 1.52-1.36 (m,11H), 1.29 (dq, J=20.6, 7.0, 6.5 Hz, 1H), 1.13-0.97 (m, 1H), 0.50 (dt,J=5.5, 3.0 Hz, 1H), 0.33-0.21 (m, 1H).

Step 6

Compound 12-F (850 mg, 3.18 mmol) in THF (6 mL) was stirred at 0° C. as2.0 M LiBH₄ in THF (3.2 mL, 6.4 mmol) was added. After 5 min, thetemperature was raised to room temperature and the reaction was allowedto proceed for 7 hours. The reaction was quenched with ice and dilutedwith EtOAc and saturated NH₄Cl. The aqueous and organic phases wereseparated. The aqueous fraction was extracted with EtOAc and the twoorganic fractions were washed with water, combined, dried (Na₂SO₄), andconcentrated. The crude product alcohol was used as is for the nextstep.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for Chemical Formula: C13H21NO3.

Molecular Weight: 239.31; found: 239.72.

A solution of the above alcohol (760 mg, 3.18 mmol), phthalimide (701mg, 4.77 mmol), and PPh₃ (1.67 g, 6.36 mmol) in THF (20 mL) was stirredat 0° C. as DIAD (1.3 mL, 6.36 mmol) was added. After addition, themixture was stirred at 0° C. for 30 min and then at room temperatureovernight. The reaction was diluted with EtOAc and washed with saturatedNH₄Cl twice. After the aqueous and organic phases were separated, theaqueous fraction was extracted with EtOAc and the two organic fractionswere combined, dried (Na₂SO₄), and concentrated. The crude product waspurified using CombiFlash (silica gel column) with 0-50% EtOAc/Hexane aseluents to provide compound 12-G. 1H NMR indicated a mixture of tworotamers.

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for Chemical Formula: C21H24N2O4,Molecular Weight: 368.43; found: 368.81.

¹H NMR (400 MHz, Chloroform-d) δ 7.95-7.58 (m, 4H), 4.32-4.05 (m, 1H),4.07-3.79 (m, 1H), 3.66 (s, 2H), 2.42 (d, J=2.2 Hz, 1H), 1.65-1.15 (m,11H), 1.10 (d, J=11.5 Hz, 1H), 0.87 (d, J=40.7 Hz, 1H), 0.45 (dt, J=6.5,3.2 Hz, 1H), 0.18 (q, J=7.0 Hz, 1H).

Step 7

Hydrazine hydrate was added to a solution of the compound 12-G in EtOHat room temperature; the reaction was stirred at 75° C. for ˜3 hours.The resulting mixture was cooled to room temperature and diluted withethyl ether (30 mL) and stirred at 0° C. for 60 min before filtration.The resulting filtrate was concentrated to provide compound 12-H.LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for Chemical Formula: C13H22N2O2,Molecular Weight: 238.33 found: 238.87.

Step 8

A mixture of 12-H 2.85 mmol), 12-I (913 mg, 2.87 mmol), and NaHCO₃ (482mg, 5.74 mmol) in water (10 mL) and EtOH (20 mL) was stirred at roomtemperature overnight. The mixture was diluted with brine and extractedwith EtOAc (twice). The extracts were combined, dried (MgSO₄),concentrated, and dried under vacuum for 30 min.

To a solution of the above crude reactant (1.6 g) in CH₂Cl₂ (10 mL) wasadded 4 N HCl in dioxane (10 mL). The reaction was stirred for about 2hours, concentrated to dryness, co-evaporated with toluene, and driedunder vacuum for 30 min.

The mixture of the above crude reactant (2.87 mmol) and DBU (4.3 mL,28.7 mmol) in MeOH (30 mL) was stirred at 60° C. bath for 120 min. Themixture was concentrated and the residue was purified by CombiFlash onsilica gel using 0-20% MeOH/EtOAc as eluents to provide 12-J.

¹H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.65 (s, 1H), 7.34 (s,2H), 5.56 (d, J=9.7 Hz, 1H), 5.14 (d, J=9.9 Hz, 1H), 5.02 (s, 1H), 4.39(d, J=7.2 Hz, 2H), 3.96 (d, J=11.6 Hz, 1H), 3.74 (d, J=29.1 Hz, 1H),2.68 (s, 1H), 2.04 (s, 1H), 1.56 (d, J=4.6 Hz, 2H), 1.45-1.20 (m, 4H),1.11 (d, J=14.1 Hz, 2H), 0.58 (s, 1H), 0.38 (s, 1H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for Chemical Formula: C24H24N2O5,Molecular Weight: 420.46; found: 421.29.

Step 9

A mixture of 12-J (752 mg, 1.841 mmol) in THF (4 mL) and MeOH (4 mL) wasstirred at room temperature as 1N KOH (3.75 mL) was added. After 1 hour,the reaction mixture was acidified with 3N HCl (1 mL), and diluted withbrine before extraction with EtOAc. The combined extracts was dried(MgSO₄) and concentrated.

To the mixture of the above crude reactant (158 mg, 0.403 mmol) in DCM(4 mL) were added 2,4,6-trifluorobenzyl amine (85 mg, 0.52 mmol), andHATU (230 mg, 0.604 mmol) at room temperature followed by DIPEA (0.3 mL,1.6 mmol). After about 60 min, the reaction mixture was diluted withDCM, washed with saturated NaHCO₃, dried (MgSO₄), and concentrated. Theresidue was purified by CombiFlash on silica gel using 0-20% MeOH/EtOActo provide compound 12-H.

Step 10

Compound 12-H (174 mg, 0.325 mmol) was dissolved in TFA (2 mL) at roomtemperature and stirred for 30 min. The solution was concentrated andthe residue was purified by CombiFlash (silica gel column) using 0-20%MeOH in CH₂Cl₂ to provide compound 12.

¹H NMR (400 MHz, Chloroform-d) δ 10.37 (t, J=5.5 Hz, 1H), 8.29 (s, 1H),6.65 (dd, J=8.8, 7.4 Hz, 2H), 4.94 (s, 1H), 4.65 (d, J=5.7 Hz, 2H), 4.13(s, 1H), 3.81 (d, J=5.2 Hz, 2H), 2.79 (s, 1H), 1.40 (d, J=10.9 Hz, 2H),1.18 (d, J=12.5 Hz, 2H), 0.64 (dt, J=6.7, 3.1 Hz, 1H), 0.45 (q, J=7.3Hz, 1H).

¹⁹F NMR (376 MHz, cdcl3) δ −109.13 to −109.21 (1F), −111.98 to −112.02(2F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for Chemical Formula: C22H18F3N3O4,Molecular Weight: 445.39; found: 446.26.

Example 13 Preparation of Compound 13(1aR,2R,10aR,11S,11aS)-5-hydroxy-4,6-dioxo-N-(2,4,5-trifluorobenzyl)-1a,2,4,6,10,10a,11,11a-octahydro-1H-2,11-methanocyclopropa[4,5]pyrido[1,2-a]pyrido[1,2-d]pyrazine-7-carboxamide

Step 1

A mixture of 12-J (752 mg, 1.841 mmol) in THF (4 mL) and MeOH (4 mL) wasstirred at room temperature as 1N KOH (3.75 mL) was added. After 1 hour,the reaction mixture was acidified with 3N HCl (1 mL), and diluted withbrine before extraction with EtOAc. The combined extracts was dried(MgSO₄) and concentrated.

To the mixture of the above crude reactant (158 mg, 0.403 mmol) in DCM(4 mL) were added the benzyl amine (85 mg, 0.52 mmol), and HATU (230 mg,0.604 mmol) at room temperature followed by DIPEA (0.3 mL, 1.6 mmol).After about 60 min, the reaction mixture was diluted with DCM, washedwith saturated NaHCO₃, dried (MgSO₄), and concentrated. The residue waspurified by CombiFlash on silica gel using 0-20% MeOH/EtOAc to providecompound 13-A.

Step 2

Compound 13-A (118 mg, 0.22 mmol) was dissolved in TFA (2 mL) at roomtemperature and stirred for 30 min. The solution was concentrated andthe residue was purified by CombiFlash (silica gel column) using 0-20%MeOH in CH₂Cl₂ to provide compound 13.

¹H NMR (400 MHz, Chloroform-d) δ 11.74 (s, 1H), 10.45 (s, 1H), 8.29 (s,1H), 7.25-7.16 (m, 1H), 6.90 (td, J=9.5, 6.4 Hz, 1H), 4.95 (s, 1H), 4.60(d, J=6.0 Hz, 2H), 4.23-4.05 (m, 1H), 3.84 (dd, J=4.2, 2.4 Hz, 2H), 2.80(d, J=3.2 Hz, 2H), 1.42 (d, J=10.9 Hz, 2H), 1.29-1.12 (m, 2H), 0.65 (dt,J=6.8, 3.2 Hz, 1H), 0.46 (q, J=7.3 Hz, 1H).

¹⁹F NMR (376 MHz, cdcl3) δ −120.67, −136.05, −143.22 to −143.36.

LCMS-ESI⁺ (m/z): [M+H]+ calculated for Chemical Formula: C22H18F3N3O4,Molecular Weight: 445.39; found: 446.29.

Antiviral Assay Example 14 Antiviral Assays in MT4 Cells

For the antiviral assay utilizing MT4 cells, 0.4 μL of 189X testconcentration of 3-fold serially diluted compound in DMSO was added to40 μL of cell growth medium (RPMI 1640, 10% FBS, 1%penicillin/streptomycin, 1% L-Glutamine, 1% HEPES) in each well of384-well assay plates (10 concentrations) in quidruplicate.

1 mL aliquots of 2×10⁶ MT4 cells are pre-infected for 1 and 3 hoursrespectively at 37° C. with 25 μL (MT4) or of either cell growth medium(mock-infected) or a fresh 1:250 dilution of an HIV-IIIb concentratedABI stock (0.004 m.o.i. for MT4 cells). Infected and uninfected cellsare diluted in cell growth medium and 35 μL of 2000 (for MT4) cells isadded to each well of the assay plates.

Assay plates were then incubated in a 37° C. incubator. After 5 days ofincubation, 25 μL of 2× concentrated CellTiter-Glo™ Reagent (catalog #G7573, Promega Biosciences, Inc., Madison, Wis.) was added to each wellof the assay plate. Cell lysis was carried out by incubating at roomtemperature for 2-3 minutes, and then chemiluminescence was read usingthe Envision reader (PerkinElmer).

Compounds of the present invention demonstrate antiviral activity inthis assay as depicted in Table 1 below. Accordingly, the compounds ofthe invention may be useful for treating the proliferation of the HIVvirus, treating AIDS, or delaying the onset of AIDS or ARC symptoms.

TABLE 1 Compound nM in MT-4 Number EC₅₀ CC₅₀ 1 9.6 14113 2 10.7 7804 39.9 4099 4 8.4 12829 5 1.6 50481 6 1.5 14062 7 2.7 4826 8 1.4 8843 9 1.410677 10 1.7 7587 11 1.5 10977 12 2.9 22792 13 2.3 7051

The data in Table 1 represent an average over time for each compound.For certain compounds, multiple assays have been conducted over the lifeof the project.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification areincorporated herein by reference, in their entirety to the extent notinconsistent with the present description.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

What is claimed is:
 1. A compound having the following Formula (I):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl;R¹ is phenyl substituted with one to three halogen atoms; X is —O—,—NR²—, —CHR³— or a bond; R² and R³ are each, independently, hydrogen orC₁₋₃alkyl; and L is —C(R^(a))₂C(R^(a))₂—; and each R^(a) is,independently, hydrogen, halo, hydroxyl, or C₁₋₄alkyl, and wherein twoR^(a) groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a carbocyclic ring having the followingstructure:

wherein each R^(b) is, independently, hydrogen or halo.
 2. A compound ofclaim 1 having the following Formula (Ia):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl;R¹ is phenyl substituted with one to three halogen atoms; X is —O—,—NR²—, —CHR³— or a bond; R² and R³ are each, independently, hydrogen orC₁₋₃alkyl; and L is —C(R^(a))₂C(R^(a))₂—; and each R^(a) is,independently, hydrogen, halo, hydroxyl, or C₁₋₄alkyl, and wherein twoR^(a) groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a carbocyclic ring having the followingstructure:

wherein each R^(b) is, independently, hydrogen or halo.
 3. A compound ofclaim 1 having the following Formula (Ib):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl;R¹ is phenyl substituted with one to three halogen atoms; X is —O—,—NR²—, —CHR³— or a bond; R² and R³ are each, independently, hydrogen orC₁₋₃alkyl; and L is —C(R^(a))₂C(R^(a))₂—; and each R^(a) is,independently, hydrogen, halo, hydroxyl, or C₁₋₄alkyl, and wherein twoR^(a) groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a carbocyclic ring having the followingstructure:

wherein each R^(b) is, independently, hydrogen or halo.
 4. A compound ofclaim 1 having the following Formula (Ic):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl;R¹ is phenyl substituted with one to three halogen atoms; X is —O—,—NR²—, —CHR³— or a bond; R² and R³ are each, independently, hydrogen orC₁₋₃alkyl; and L is —C(R^(a))₂C(R^(a))₂—; and each R^(a) is,independently, hydrogen, halo, hydroxyl, or C₁₋₄alkyl, and wherein twoR^(a) groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a carbocyclic ring having the followingstructure:

wherein each R^(b) is, independently, hydrogen or halo.
 5. A compound ofclaim 1 having the following Formula (Id):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl;R¹ is phenyl substituted with one to three halogen atoms; X is —O—,—NR²—, —CHR³— or a bond; R² and R³ are each, independently, hydrogen orC₁₋₃alkyl; and L is —C(R^(a))₂C(R^(a))₂—; and each R^(a) is,independently, hydrogen, halo, hydroxyl, or C₁₋₄alkyl, and wherein twoR^(a) groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a carbocyclic ring having the followingstructure:

wherein each R^(b) is, independently, hydrogen or halo.
 6. A compound ofclaim 1 having the following Formula (Ie):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:Y¹ and Y² are each, independently, hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl;R¹ is phenyl substituted with one to three halogen atoms; X is —O—,—NR²—, —CHR³— or a bond; R² and R³ are each, independently, hydrogen orC₁₋₃alkyl; and L is —C(R^(a))₂C(R^(a))₂—; and each R^(a) is,independently, hydrogen, halo, hydroxyl, or C₁₋₄alkyl, and wherein twoR^(a) groups on adjacent carbon atoms, together with the carbon atoms towhich they are attached, form a carbocyclic ring having the followingstructure:

wherein each R^(b) is, independently, hydrogen or halo.
 7. A compound ofany one of claims 1-6 wherein X is —O—.
 8. A compound of any one ofclaims 1-6 wherein X is —NH—.
 9. A compound of any one of claims 1-6wherein X is —CH₂—.
 10. A compound of any one of claims 1-6 wherein X isa bond.
 11. A compound of any one of claims 1-11 wherein Y¹ is C₁₋₄alkyland Y² is hydrogen.
 12. A compound of claim 11 wherein Y¹ is methyl andY² is hydrogen.
 13. A compound of any one of claims 1-5 wherein Y¹ isC₁₋₄haloalkyl and Y² is hydrogen.
 14. A compound of claim 13 wherein Y¹is CF₃ and Y² is hydrogen.
 15. A compound of any one of claims 1-11wherein Y¹ is hydrogen, methyl or CF₃ and Y² is hydrogen.
 16. A compoundof any one of claims 1-11 wherein Y¹ and Y² are both hydrogen.
 17. Acompound of any one of claims 1-16 wherein R¹ is substituted with onehalogen.
 18. A compound of claim 17 wherein R¹ is 4-fluorophenyl or2-fluorophenyl.
 19. A compound of any one of claims 1-16 wherein R¹ issubstituted with two halogens.
 20. A compound of claim 19 wherein R¹ is2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl,3-fluoro-4-chlorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or3,5-difluorophenyl.
 21. A compound of claim 20 wherein R¹ is2,4-difluorophenyl.
 22. A compound of any one of claims 1-16 wherein R¹is substituted with three halogens.
 23. A compound of claim 22 whereinR¹ is 2,4,6-trifluorophenyl, 2,3,4-trifluorophenyl, or2,4,5-trifluorophenyl.
 24. A compound of claim 22 wherein R¹ is2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl.
 25. A compound of claim24 wherein R¹ is 2,4,6-trifluorophenyl.
 26. A compound of claim 24wherein R¹ is 2,4,5-trifluorophenyl.
 27. A compound of any one of claims1-26 wherein each R^(b) is independently hydrogen.
 28. A compound of anyone of claims 1-26 wherein each R^(b) is independently halogen.
 29. Acompound of claim 28 wherein each R^(b) is fluoro.
 30. A compound ofclaim 1 that is:


31. A compound of claim 1 that is:


32. A pharmaceutical composition comprising a compound of any one ofclaims 1-31, or a stereoisomer or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, diluent orexcipient.
 33. A pharmaceutical composition of claim 32 furthercomprising one to three additional therapeutic agents.
 34. Apharmaceutical composition of claim 33 wherein the one to three oneadditional therapeutic agents is an anti-HIV agent.
 35. A pharmaceuticalcomposition of claim 33 wherein the one to three additional therapeuticagents is selected from the group consisting of HIV protease inhibitors,HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleosideor nucleotide inhibitors of reverse transcriptase, and combinationsthereof.
 36. A pharmaceutical composition of claim 32, furthercomprising a first additional therapeutic agent selected from the groupconsisting of: abacavir sulfate, tenofovir, tenofovir disoproxilfumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarateand a second additional therapeutic agent selected from the groupconsisting of emtricitibine and lamivudine
 37. A method of treating anHIV infection in a human having or at risk of having the infection byadministering to the human a therapeutically effective amount of acompound of any one of claims 1-31 or a pharmaceutical composition ofany one of claims 32 to
 36. 38. Use of a compound of any one of claims1-31 or a pharmaceutical composition of any one of claims 32 to 36 forthe treatment of an HIV infection in a human having or at risk of havingthe infection.
 39. A compound as described in any one of claims 1-31, ora pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of any one of claims 32 to 36 for use in medical therapy.40. A compound as described in any one of claims 1-31, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of any one of claims 32 to 36 for use in the prophylactic ortherapeutic treatment of an HIV infection.